Meta-diarylaniline or meta-diarylpyridinamine compound, preparation method and medical uses thereof

ABSTRACT

Meta-diarylaniline or meta-diarylpyridinamine compounds, methods for preparing the same and uses thereof in manufacture of a medicament. The compounds according to the present application have strong inhibitory activity (at nM level) against wild-type and various drug-resistant HIV viral strains, exhibit good druggability, and can be easily synthesized.

FIELD OF THE INVENTION

The invention, which belongs to pharmaceutical and chemical engineeringfield, relates to meta-diarylaniline or meta-diarylpyridinaminecompounds, methods for preparing the same and medical uses thereof. Inparticular, the invention relates to meta-diarylanilines (DAANs) andmeta-diarylpyridinamines (DAPAs) compounds having anti-HIV activity,methods for preparing the same, pharmaceutical compositions comprisingthe same, and uses thereof in manufacture of anti-HIV drugs.

BACKGROUND OF THE INVENTION

Acquired Immune Deficiency Syndrome (AIDS) is a globally popular lethalinfectious disease caused by Human Immunodeficiency Virus (HIV). HIV isa RNA virus, which destroys the immune system in human by infectingimmunocytes in human and leads to complete loss of immune function inhuman, so that patients die of diseases caused by a variety ofinfections. Based on different drug targets involved in the replicationof HIV virus, almost 30 anti-HIV drugs have been developed successfullyby far. Said drugs can be divided into 5 classes depending on mechanismof action, i.e. Nucleoside Reverse Transcriptase Inhibitors (NRTIs),Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), ProteaseInhibitors (PIs), fusion inhibitors (Enfuvirtide) and entry inhibitors(Maraviroc). There are already 5 commercially available NNRTIs, whichuse HIV reverse transcriptase as target, i.e. Nevirapine, Delavirdine,Efavirenz, Entravine (TMC125), and Rilpivirine (TMC278). Drugs of thisclass is non-competitive inhibitors, has superiority with respect tohigh efficiency, low toxicity and good synergistic effect with otherclasses of anti-HIV drugs, and play an important role in anti-HIVcombination therapy (HAART). Since variation constantly occurs in HIVvirus due to action of drugs, new drug-resistant viral strains appearcontinuously, which is the main problem of anti-HIV drugs. Therefore, itis very necessary and extremely urgent to look for and develop novelanti-HIV drugs having strong inhibitory activity against drug-resistantviruses.

DESCRIPTION OF THE INVENTION

The inventors further modify the structures of two anti-HIV leadcompounds (i.e. meta-diarylanilines (DAANs) and meta-diarylpyridinamines(DAPDs)) to obtain novel compounds having strong inhibitory activity (atnM level) against wild-type and various drug-resistant HIV viral strains(see Tables 2 and 3 for a part of data) through deep study and creativework. Moreover, the novel active compounds also exhibit gooddruggability (see Table 3 for a part of data). The novel compoundsaccording to the invention have high efficiency, low toxicity, goodwater solubility, logP value (<5), and metablic stability (t_(1/2)),which faciliate absorption and efficacy of the drugs in vivo. Thecompounds according to the invention have the potential to be anti-HIVdrugs. Thus, the following invention is provided.

In one aspect, the invention relates to a compound of formula (I) or apharmaceutically acceptable salt thereof,

wherein

R₁ is —NH₂, —OH, halogen (such as fluoroine, chlorine, bromine oriodine), —NO₂, —CN, —COOH, —SO₃H, —OCH₃, —CH₃ or —CF₃;

R₂ is H;

R₃ is H, OH, halogen (such as fluoroine, chlorine, bromine or iodine),—NH₂, cyano, triazo, ethynyl, —NO₂, —COOH, —SO₃H, —CF₃, vinyl, C₁₋₄acyl, C₁₋₄ ester group, trifluoroacetoxyl, C₁₋₄ acyloxy, OCONH₂,OCONHCH₃, uramido, guanido, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₁₋₆haloalkyl, C₁₋₆ aminoalkyl, C₁₋₆ ether alkyl, C₁₋₆ alkoxy, C₁₋₆hydroxyalkoxy, C₁₋₆ haloalkoxy, C₁₋₆ aminoalkoxy, C₁₋₆ ether alkoxy,C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆ ether alkylamino, C₃₋₈cycloalkyl, C₃₋₈ cyclylalkoxy, C₃₋₈ cyclylalkylamino, heterocyclyl (suchas piperidyl, piperazinyl, morpholinyl or epoxyalkyl), 3- to 8-memberedheterocyclyl substituted with C₁₋₄ hydroxyalkyl or C₁₋₄ haloalkyl orC₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl, 3- to 8-memberedheterocyclylalkyl substituted with C₁₋₄ hydroxyalkyl or C₁₋₄ haloalkylor C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl, 3- to8-membered heterocyclylalkoxy substituted with C₁₋₄ hydroxyalkyl or C₁₋₄haloalkyl or C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl, or3- to 8-membered heterocyclylalkylamino substituted with C₁₋₄hydroxyalkyl or C₁₋₄ haloalkyl or C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl orC₁₋₄ ether alkyl;

R₄ is —CN, —NH₂, —OH, halogen (such as fluoroine, chlorine, bromine oriodine), —NO₂, —COOH, —SO₃H, —OCH₃, —CH₃, —CF₃, vinyl, ethynyl, triazo,cyanovinyl or cyanoethynyl;

R₅ is C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen (such as fluoroine, chlorine,bromine or iodine) or C₁₋₆ haloalkyl;

R₆ is C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen (such as fluoroine, chlorine,bromine or iodine) or C₁₋₆ haloalkyl;

R₆ and R₅ are identical or different;

R₇ is —NH₂, —OH, halogen (such as fluoroine, chlorine, bromine oriodine), —NO₂, —CN, —COOH, —SO₃H, —OCH₃, —CH₃, —CH═CH—CN, or —CF₃; or R₇is —NH₂, —OH, halogen (such as fluoroine, chlorine, bromine or iodine),—NO₂, —CN, —OCH₃, —CH₃, —CH═CH—CN, or —CF₃, which is linked to 1, 2, 3or 4 —CH₂—; or R₇ is C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl,C₁₋₆ cyanoalkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₁₋₆ ether alkoxy, C₂₋₆ alkenyl or alkynyl,ene-ene-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl,ene-yne-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl,ene-carbonyl-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl,yne-carbonyl-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl,C₁₋₆ hydrocarbonyl substituted with one or more hydroxyl or halogen;

X is —NH— or —O—;

Y is —CH— or —N—;

m is 0, 1, 2, 3 or 4.

In another aspect, the invention relates to a compound of formula (II)or a pharmaceutically acceptable salt thereof,

wherein

R₁ is —NH₂, —OH, halogen (such as fluoroine, chlorine, bromine oriodine), —NO₂, —CN, —COOH, —SO₃H, —OCH₃, —CH₃ or —CF₃;

R₂ is H;

R₃ is H, OH, halogen (such as fluoroine, chlorine, bromine or iodine),—NH₂, cyano, triazo, ethynyl, —NO₂, —COOH, —SO₃H, —CF₃, vinyl, C₁₋₄acyl, C₁₋₄ ester group, trifluoroacetoxyl, C₁₋₄ acyloxy, OCONH₂,OCONHCH₃, uramido, guanido, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₁₋₆haloalkyl, C₁₋₆ aminoalkyl, C₁₋₆ ether alkyl, C₁₋₆ alkoxy, C₁₋₆hydroxyalkoxy, C₁₋₆ haloalkoxy, C₁₋₆ aminoalkoxy, C₁₋₆ ether alkoxy,C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆ ether alkylamino, C₃₋₈cycloalkyl, C₃₋₈ cyclylalkoxy, C₃₋₈ cyclylalkylamino, heterocyclyl (suchas piperidyl, piperazinyl, morpholinyl or epoxyalkyl), 3- to 8-memberedheterocyclyl substituted with C₁₋₄ hydroxyalkyl or C₁₋₄ haloalkyl orC₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl, 3- to 8-memberedheterocyclylalkyl substituted with C₁₋₄ hydroxyalkyl or C₁₋₄ haloalkylor C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl, 3- to8-membered heterocyclylalkoxy substituted with C₁₋₄ hydroxyalkyl or C₁₋₄haloalkyl or C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl, or3- to 8-membered heterocyclylalkylamino substituted with C₁₋₄hydroxyalkyl or C₁₋₄ haloalkyl or C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl orC₁₋₄ ether alkyl;

R₄ is H, —CN, —NH₂, —OH, halogen (such as fluoroine, chlorine, bromineor iodine), —NO₂, —COOH, —SO₃H, —OCH₃, —CH₃, —CF₃, vinyl, ethynyl,triazo, cyanovinyl or cyano ethynyl;

R₅ and R₆ each are independently C₁₋₆ alkyl, C₁₋₆ alkoxy; halogen (suchas fluoroine, chlorine, bromine or iodine) or C₁₋₆ haloalkyl;

R₆ and R₅ are identical or different;

R₇ is —NH₂, —OH, halogen (such as fluoroine, chlorine, bromine oriodine), —NO₂, —CN, —COOH, —SO₃H, —OCH₃, —CH₃, —CH═CH—CN, or —CF₃; or R₇is —NH₂, —OH, halogen (such as fluoroine, chlorine, bromine or iodine),—NO₂, —CN, —OCH₃, —CH₃, —CH═CH—CN, or —CF₃, which is linked with 1, 2, 3or 4 —CH₂—; or R₇ is C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl,C₁₋₆ cyanoalkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₁₋₆ ether alkoxy, C₂₋₆ alkenyl or alkynyl,ene-ene-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl,ene-yne-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl,ene-carbonyl-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl,yne-carbonyl-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl,C₁₋₆ hydrocarbonyl substituted with one or more hydroxyl or halogen;

m is 0, 1, 2 or 3;

X is —NH— or —O—;

Y is —CH— or —N—.

The compound or pharmacutical salt thereof according to any item of theinvention, wherein

R₁ is —NH₂, —OH, —F, —Cl, —Br, —I, —NO₂, —CN, —COOH, —SO₃H, —OCH₃, —CH₃or —CF₃;

R₂ is H;

R₃ is —CF₃, —CCl₃, —CBr₃, —NO₂, —COOCH₃, —COOCH₂CH₃, —COOCH₂CH₂CH₃,—COOH, —CONH₂, —CONHCH₃, —SO₂NH₂, H, —NH₂, —CONHNH₂, —OH, —F, —Cl, —Br,—I, —NO₂, —CN, —SO₃H, —OCH₃, —CH₃, —CH₂OH, —CH₂OR′, —CH₂NH₂, or—CH₂NHR′; wherein R′ is

R₄ is —CN, —NH₂, —OH, —F, —Cl, —Br, —I, —NO₂, —COOH, —SO₃H, —OCH₃, —CH₃or —CF₃;

R₅ is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy,isopropoxy, fluoro, chloro, bromo, or iodo;

R₆ is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy,isopropoxy, fluoro, chloro, bromo, or iodo;

R₆ and R₅ are identical or different;

R₇ is —(CH₂)₂—CN, —(CH₂)₂—CH₃, —(CH₂)₂—COOCH₃, —(CH₂)₃—OH, —(CH₂)₂

—(CH₂)₃—CN, —(CH₂)₃—CH₃, —(CH₂)₃—COOCH₃, —(CH₂)₂—OH, —(CH₂)₃

—(CH₂)₄—CN, —(CH₂)₄—CH₃, —(CH₂)₄—COOCH₃, —(CH₂)₄—OH, —(CH₂)₄

—CH₂—CN, —CH₂—CH₃, —CH₂—COOCH₃, —CH₂—OH, —CH₂

or —CH₂OR″; wherein R″ represents C₁₋₆alkyl;

X is —NH— or —O—;

Y is —CH— or —N—;

the other symbols are defined as they are in any of the preceding items.

The compound or pharmacutical salt thereof according to any item of theinvention, wherein

R₁ is —NH₂;

R₂ is H;

R₃ is —CF₃, —COOCH₃, —COOH, —CONH₂, —CONHCH₃, —SO₂NH₂, H, —NH₂,—CONHNH₂; —OH, —F, —Cl, —Br, —I, —NO₂, —CN, —SO₃H, —OCH₃, —CH₃, —CH₂OH,—CH₂OR′, —CH₂NH₂, —CH₂NHR′, —CH₂Cl or —CH₂Br;

R₄ is —CN;

R₅ is methyl, methoxy, fluoro, chloro, or bromo;

R₆ is methyl, methoxy, fluoro, chloro, or bromo;

R₆ and R₅ are identical or different;

R₇ is —(CH₂)₂—CN, —(CH₂)₂—CH₃, —(CH₂)₂—COOCH₃, —(CH₂)₃—OH or —(CH₂)₂

X is —O—;

Y is —CH— or —N—;

the other symbols are defined as they are in any of the preceding items.

The compound or pharmacutical salt thereof according to any item of theinvention, selected from the compounds in Table 1 or pharmaceuticallyacceptable salts thereof:

TABLE 1 Some compounds of the invention Com- pound No. Name Structure  25-(4″-cyanoethyl-2″, 6″-dimethyl- phenoxy)-N¹-(4′-cyanophenyl)-4-trifluoromethyl-1,2-phenylene-- enediamine

 4 5-(4″-cyanoethyl-2″, 6″-dimethyl- phenoxy)-N¹-(4′-cyanophenyl)-4-methoxycarbonyl-1,2-phenylene- diamine

 6 5-(4″-cyanoethyl-2″, 6″-dimethyl- phenoxy)-N¹-(4′-cyanophenyl)-4-hydroxymethyl-1,2-phenylene- diamine

 8 4-carboxyl-5-(4″-cyanoethyl-2″, 6″- dimethylphenoxy)-N¹-(4′-cyanophenyl)-1,2-phenylene- diamine

10 4-carbamoyl-N¹-(4′-cyanophenyl)- 5-(4″-cyanoethyl-2″, 6″-dimethylphenyoxy)-1,2-phenylene- diamine

12 5-(4″-cyanoethyl-2″, 6″-dimethyl- phenoxy)-N¹-(4′-cyanophenyl)-4-(N-methyl-carbamoyl)-1,2- phenylenediamine

14 5-(4″-cyanoethyl-2″, 6″-dimethyl- phenoxy)-N¹-(4′-cyanophenyl)-4-aminosulfonyl-1,2- phenylenediamine

16 N²-(4-cyanoanilinyl)-6-(2,6-di- methyl-4-propylphenoxy)-3-aminopyridine

17 N-(4′-cyanophenyl)-5-(4″-hydroxy- methyl-2″, 6″-dimethylphenoxy)-4-hydroxymethyl-2-nitroaniline

18 N¹-(4′-cyanophenyl)-5-(4″-hydroxy- methyl-2″, 6″-dimethylphenoxy)-4-hydroxymethyl-1,2-phenylene- diamine

21 N²-(4-cyanoanilinyl)-6-(2,6-di- fluoro-4-cyanoethyl-phenoxy)-3-aminopyridine

23 N²-(4-cyanoanilinyl)-6-(2,6-di- fluoro-4-methyl propionate-phenoxy)-3-aminopyridine

24 N²-(4-cyanoanilinyl)-6-(2,6-di- fluoro-4-(3-hydroxypropyl)phenoxy)-3-aminopyridine

26A 6-(2-bromo-4-cyanoethyl-5- methoxy)phenoxy-2-(4-cyano-anilinyl)-3-aminopyridine

26B 6-(2-bromo-4-cyanovinyl-5- methoxy)phenoxy-2-(4-cyano-anilinyl)-3-aminopyridine

28 2-(4-cyanoanilinyl)-6-(2,6- dibromo-4-cyanoethyl)phenoxy-3-aminopyridine

30 N²-(4-cyanoanilinyl)-6-(2,6-di- fluoro-4-butanoylphenoxy)-3-aminopyridine

33 N¹-(4′-cyanophenyl)-5-(4″-cyano- vinyl-2″, 6″-dimethylphenoxy)-4-[(2-methoxyethoxy)methyl]- 1,2-phenylenediamine

34 N¹-(4′-cyanophenyl)-5-(4″-cyano- ethyl-2″, 6″-dimethylphenoxy)-4-[N-cyclopropylaminomethyl]- 1,2-phenylenediamine

35 N¹-(4′-cyanophenyl)-5-(4″-cyano- ethyl-2″, 6″-dimethylphenoxy)-1,2,4-triaminobenzene

36 N¹-(4′-cyanophenyl)-5-(4″-cyano- ethyl-2″, 6″-dimethylphenoxy)-4-formhydrazide- 1,2-phenylenediamine

37 4-acetyloxymethyl-N¹-(4′-cyano- phenyl)-5-(4″-cyanoethyl-2″, 6″-dimethylphenoxy)-1,2-phenyl- enediamine

38 N¹-(4′-cyanophenyl)-5-(4″-cyano- ethyl-2″, 6″-dimethylphenoxy)-4-[methoxymethyl]-1,2- phenylenediamine

39 N¹-(4′-cyanophenyl)-5-(4″-cyano- ethyl-2″, 6″-dimethylphenoxy)-4-cyclopropionyloxymethyl-1,2- phenylenediamine

40 N¹-(4′-cyanophenyl)-5-(4″-cyano- ethyl-2″, 6″-dimethylphenoxy)-4-[N,N-dimethylaminomethyl]- 1,2-phenylenediamine

41 N¹-(4′-cyanophenyl)-5-(4″-cyano- ethyl-2″, 6″-dimethylphenoxy)-4-(N-ethylformamido)-1,2- phenylenediamine

42 5-(4″-cyanoethyl-2″, 6″-dimethyl- phenoxy)-N¹-(4′-cyanophenyl)-4-(N,N-dimethylformamido)-1,2- phenylenediamine

43 N¹-(4′-cyanophenyl)-5-(4″-cyano- ethyl-2″, 6″-dimethylphenoxy)-4-(N-cyclopropylformamido)-1,2- phenylenediamine

The compound according to the invention may be used directly or in aform of a pharmaceutically acceptable salt or a solvate thereof. Apharmaceutically acceptable salt of the compound according to theinvention includes a conventional salt formed with a pharmaceuticallyacceptable inorganic or organic acid, or inorganic or organic base.Examples of suitable acid addition salts include salts formed byhydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid,succinic acid, glycolic acid, formic acid, lactic acid, maleic acid,tartaric acid, citric acid, pamoic acid, malonic acid, hydroxymaleicacid, toluylic acid, glutamic acid, benzoic acid, salicylic acid,fumaric acid, toluene sulfonic acid, methylsulfonic acid,naphthalene-2-sulfonic acid, benzenesulfonic acid, naphtholcarboxylicacid, hydriodic acid, malic acid, tannin, and the like. Examples ofsuitable base addition salts include salts formed by Na, Li, K, Mg, Al,Ca, Zn, N,N′-dibenzylethylenediamine, chloro-substituted procaine,choline, diethanol amine, ethanediamine, N-methylglucosamine, procaineand the like. When the compound according to the invention is mentioned,it refers to the compound according to the invention and apharmaceutically acceptable salt or solvate thereof.

In another aspect, the invention relates to a method for preparing acompound according to any item of the invention. The scheme is shown asfollows:

wherein R₁, R₂, R₃, R₄, X and Y, and m are defined as they are in any ofthe preceding items; the method comprises reacting a substituted2,6-dihalo benzene or pyridine compound with a p-substituted anilinecompound under basic (K₂CO₃) condition, or using excessive 4-cyanoaniline to carry out a solvent-free reaction to produce the intermediateof formula II or III; coupling with a 1,3,5-trisubstituted phenol oraniline compound under basic (K₂CO₃, Cs₂CO₃, NaH or potassiumt-butoxide) condition to get an intermediate (IV or V) having a tricyclebackbone structure, then converting the substituent (R₁) of theintermediate ring to the corresponding group through conventionalfunctional-group conversion reaction (such as oxidization, reduction,substitution or coupling), and finally reducing the nitro group on theintermediate ring to an amino group.

In a further aspect, the invention relates to a pharmaceuticalcomposition, comprising the compound or pharmaceutically acceptable saltthereof according to any item of the invention; optionally, thepharmaceutical composition further comprises one or morepharmaceutically acceptable carrier or excipients.

The term “composition” refers to a product comprising specifiedingredients in specified amounts, and a product generated from direct orindirect combination of specified amounts of specified ingredients.

The pharmaceutical composition according to the invention generallycomprises 0.1-90 wt % of the compound and/or pharmaceutically acceptablesalt thereof according to the invention. The pharmaceutical compositionmay be prepared according to methods known in the art. For this purpose,if necessary, the compound and/or pharmaceutically acceptable saltthereof according to the invention may be combined with one or moresolid or liquid pharmaceutical excipient and/or adjuvant to prepare anadministration form or dosage form suitable for use in human.

The compounds according to the invention or the pharmaceuticalcompositions comprising the same may be administered in a unit dosageform, and the administration route may be enteric or parenteral, such asoral, muscular, subdermal, rhinal, buccal, dermal, peritoneal or rectal,etc. The dosage forms are, for example, tablets, capsules, drop pills,aerosols, pills, powder, liquores, suspensions, emulsion, granules,liposomes, cutaneous permeable agents, buccal tablets, suppositories,lyophilized powder-injections, etc. They may be conventionalpreparations, sustained release preparations, controlled releasepreparations, and various microparticle drug delivery systems. In orderto formulate a unit dosage form into a table, a variety of carriersknown in the art may be widely used. Examples of carriers are, forexample, diluents and absorbents, such as starch, dextrin, calciumsulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea,calcium carbonate, kaoliang oil, microcrystalline cellulose, aluminiumsilicate and the like; wetting agents and binding agents, such as water,glycerol, polyethylene glycol, ethanol, propanol, starch paste, dextrin,syrup, honey, glucose solution, mucilago acaciae, gelatin slurry,carboxymethylcellulose sodium, shellack, methylcellulose, potassiumphosphate, polyvinylpyrrolidone, etc.; disintegrating agents, such asdry starch, alginate, powdered agar, laminaran, dicarbonate and citricacid, calcium carbonate, polyoxyethylene, sorbitan fatty acid ester,sodium dodecylsulphate, methylcellulose, ethyl cellulose, etc.;disintegration inhibitor, such as sucrose, tristearin, cacao butter,hydrogenated oil, etc.; absorption enhancers, such as quaternaryammonium salt, sodium dodecylsulphate, etc.; lubricants, such as talcumpowder, silicon dioxide, corn starch, stearate, boric acid, liquidparaffin, polyethylene glycol, etc. The tablets may be furtherformulated into coated tablets, such as sugar coated tablet, film coatedtablet, enteric-coated tablet, or bilayered tablets and multilayeredtablets. In order to formulate a unit dosage form into a pill, a varietyof carriers known in the art may be widely used. Examples of carriersare, for example, diluents and absorbents, such as glucose, lactose,starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone,Gelucire, kaolin, talcum powder, etc.; binding agents such as Arabicgum, bassora gum, gelatin, ethanol, honey, liquid sugar, rice paste orpanada, etc.; disintegrating agents, such as powdered agar, dry starch,alginate, sodium dodecylsulphate, methylcellulose, ethyl cellulose, etc.In order to formulate a unit dosage form into a suppository, a varietyof carriers known in the art may be widely used. Examples of carriersare, for example, polyethylene glycol, lecithin, cacao butter, higheralcohols, esters of higher alcohols, gelatin, semi-synthesizedglyceride, etc. In order to formulate a unit dosage form into acapasule, a compound or a pharmaceutically acceptable salt thereof as anactive ingredient is mixed with said carriers, and the resultant mixtureis placed in a hard gelatine capsule or a soft capsule. A compound or apharmaceutically acceptable salt thereof as an active ingredient may beformulated into a microcapsule, may be suspended in an aqueous media toform a suspension, which may be packaged into a hard capsule orformulated into an injection. In order to formulate a unit dosage forminto a formulation for use in injection, such as a liquor, an emulsion,lyophilized powder-injection and suspension, all the common diluents maybe used in the art, for example, water, ethanol, polyethylene glycol,1,3-propanediol, ethoxylated isooctadecanol, poly-oxylatedisooctadecanol, polyoxyethylene sorbitan fatty acid esters, etc. Inaddition, in order to prepare isotonic injection, a suitable amount ofsodium chloride, glucose, or glycerol may be added to the formulationfor use in injection. In addition, conventional cosolvents, buffers, pHregulators and the like may be added.

In addition, if necessary, to a pharmaceutical formulation, colorants,preservatives, flavors, flavoring agents, sweeteners or other materialsmay also be added.

The administration dose of the compound or pharmaceutically acceptablesalt thereof according to the invention depends on many factors, e.g.the nature and severity of the diseases to be prevented or treated,gender, age, weight and individual response of a patent or animal, theparticular compound used, the administration route and administrationfrequency, and the like. Said dose may be administered in one singledose or in several doses, such as in two, three or four doses.

The actual dosage level of the active ingredient in the pharmaceuticalcomposition according to the invention may be altered so that the amountof the active compound is effective to obtain a desired treatmentresponse in the case of a particular patient, a particular compositionand a particular administration route. The dosage level is selecteddepending on the activity of a particular compound, the administrationroute, the severity of the disease to be treated, and the condition andthe medical history of the patient to be treated. However, the generalmethod in the art is that the dosage of a compound starts from a levellower than the one needed for the desired therapeutic effect, andincreases gradually until the desired effect is obtained.

In a further aspect, the invention relates to use of the compound orpharmaceutically acceptable salt thereof according to any item of theinvention in manufacture of a medicament for prevention and/or treatmentand/or assistant treatment of HIV or a disease or a condition associatedwith HIV infection.

In a further aspect, the invention relates to a method for preventionand/or treatment and/or assistant treatment of HIV or a disease or acondition associated with HIV infection, comprising the step ofadministering to a subject an effective amount of the compound orpharmaceutically acceptable salt thereof according to any item of theinvention.

In a further aspect, the invention relates to use of the compound orpharmaceutically acceptable salt thereof according to any item of theinvention in manufacture of a medicament or an agent for inhibiting HIVvirus.

In a further aspect, the invention relates to a method for inhibitingHIV virus in vivo or in vitro, comprising the step of administering aneffective amount of the compound or pharmaceutically acceptable saltthereof according to any item of the invention.

The term “an amount effective for prevention and/or treatment of acompound according to the invention” refers to an amount of a compoundsufficient for the treatment of disorders in a reasonable effect/riskratio suitable for any medical prevention and/or treatment.

The term “subject” may refer to a patient or an animal that receives thecomposition according to the invention to treat, prevent, ease and/oralleviate the disease or condition according to the invention,particularly a mammal, e.g. human, dog, monkey, cattle, horse, etc.

The term “disease and/or condition” refers to a physical state of thesubject, which is associated with the disease and/or condition of theinvention.

It should be understood that the total daily amount of a compound or apharmaceutical composition according to the invention shall be decidedby an attending physician within a reliable medical range. For anyspecific patient, the therapeutically effective dosage level depends onmany factors, including the disorder to be treated and the severity ofthe disorder; the activity of the particular compound used; theparticular composition used; age, weight, general health condition,gender and diet of the patient; the administration timing,administration route and excretion rate of the particular compound used;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and similar factors well known inmedical field. For example, the general method in the art is that thedosage of a compound starts from a level lower than the one needed forthe desired therapeutic effect, and increases gradually until thedesired effect is obtained. In general, the dosage of a compoundaccording to the invention for a mammal, particularly human, is between0.001 and 1000 mg/kg weight/day, e.g. between 0.01 and 100 mg/kgweight/day, e.g. between 0.01 and 10 mg/kg weight/day.

The compounds according to the invention may effectively prevent and/ortreat the diseases or conditions as described in the invention.

In the invention,

The term “C₁₋₆ alkyl” refers to a linear or branched alkyl having 1-6carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,tent-butyl, amyl, 2-amyl, isoamyl, neo-amyl, hexyl, 2-hexyl, 3-hexyl,etc.; C₁₋₃alkyl may be understood in a similar manner. C₁₋₃alkyl ispreferred.

The term “C₁₋₆ alkoxy” refers to a linear or branched alkoxy having 1-6carbon atoms, e.g. methoxy, ethoxyl, propoxy, isopropoxy, n-butoxy,sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isoamoxy, neopentyloxy,hexyloxy, 2-hexyloxy, 3-hexyloxy etc.; C₁₋₃ alkoxy may also beunderstood in the same manner. C₁₋₃alkoxy is preferred.

The term “C₃₋₈ cycloalkyl” refers to a saturated carbon ring grouphaving 3-8 carbon atoms. The cycloalkyl may be a monocycle or apolycyclic fused system, and may be fused to an aromatic ring. Theexamples of these groups include cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl. C₃₋₆ cycloalkyl may also be understood in the samemanner. Cycloalkyl used herein may be not substituted or be substitutedwith various groups at one or more substitutable positions as describedin detail. For example, these cycloalkyl may be optionally substitutedby a group selected from the following: C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano,halogen, hydroxyl, amino group, nitro group, mono(C₁₋₆)alkylamino,di(C₁₋₆)alkylamino, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆haloalkoxy.

The term “C₁₋₆ acyl” refers to —C(O)R′, wherein R′ is selected from C₁₋₆alkyl or C₃₋₈ cycloalkyl as defined in the invention, and typicalexamples of acyl include, but are not limited to —C(O)CH₃, —C(O)C₂H₅,etc.

The term “C₁₋₆ ester group” refers to —C(O)OR′, wherein R′ is selectedfrom C₁₋₆ alkyl and C₃₋₈ cycloalkyl as defined in the invention, andtypical examples of ester group include, but are not limited to —COOCH₃,—COOC₂H₅, etc.

The term “C₁₋₆ acyloxy” refers to —OC(O)R′, wherein R′ is selected fromC₁₋₆ alkyl and C₃₋₈ cycloalkyl as defined in the invention, and typicalexamples thereof include, but are not limited to —OC(O)CH₃, —OC(O)C₂H₅,etc.

The term “C₁₋₆ hydroxyalkyl” refers to C₁₋₆ alkyl having one or morehydroxyl groups at one or more carbon atoms thereof. C₁₋₄ hydroxyalkylmay also be understood in the same manner.

The term “C₁₋₆ haloalkyl” refers to C₁₋₆ alkyl having one or morehalogen atoms at one or more carbon atoms thereof; when more halogenatoms are comprised, the halogen atoms may be identical or different.C₁₋₄ haloalkyl may also be understood in the same manner.

The term “halogen” or “halogen atom” refers to fluorine, chlorine,bromine and iodine.

The term “C₁₋₆ aminoalkyl” refers to C₁₋₆ alkyl having one or more aminogroups at one or more carbon atoms thereof. C₁₋₄ aminoalkyl may also beunderstood in the same manner.

The term “C₁₋₆ ether alkyl” refers to C₁₋₆ alkyl having one or moreoxygen atoms inserted between any two carbon atoms thereof. C₁₋₄ etheralkyl may also be understood in the same manner.

The term “C₁₋₆ cyanoalkyl” refers to C₁₋₆ alkyl having one or more cyanoinserted between any two carbon atoms thereof. C₁₋₄ cyanoalkyl may alsobe understood in a similar manner.

The term “C₁₋₆ hydroxyalkoxy” refers to a group —OR′, wherein R′ is C₁₋₆alkyl having one or more hydroxyl groups at one or more carbon atomsthereof.

The term “C₁₋₆ haloalkoxy” refers to a group —OR′, wherein R′ is C₁₋₆alkyl having one or more halogen atoms at one or more carbon atomsthereof.

The term “C₁₋₆ aminoalkoxy” refers to a group —OR′, wherein R′ is C₁₋₆alkyl having one or more amino groups at one or more carbon atomsthereof.

The term “C₁₋₆ ether alkoxy” refers to a group —OR′, wherein R′ is C₁₋₆alkyl having one or more oxygen atoms inserted between any two carbonatoms thereof.

The term “C₁₋₆ alkylamino” refers to NHR′, wherein R′ is selected fromC₁₋₆ alkyl or C₃₋₈ cycloalkyl as defined in the invention.

The term “C₁₋₆ ether alkylamino” refers to NHR′, wherein R′ is selectedfrom C₁₋₆ alkyl or C₃₋₈ cycloalkyl as defined in the invention, and hasone or more oxygen atoms inserted between any two carbon atoms of C₁₋₆alkyl or C₃₋₈ cycloalkyl.

The term “C₁₋₆ dialkylamino” refers to NR′R″, wherein R′ and R″ each areindependently selected from C₁₋₆ alkyl and C₃₋₆cycloalkyl as defined inthe invention.

The term “C₂₋₆ alkenyl” refers to an alkenyl having 2-6 carbon atoms andat least one double bond, including vinyl, propenyl, 1-buta-3-enyl,1-penta-3-enyl etc.; C₃₋₅ alkenyl may be understood in a similar manner.C₃₋₅ alkenyl is preferred.

The term “C₂₋₆ alkynyl” refers to an alkyl having 2-6 carbon atoms andat least one triple bond, including ethynyl, propinyl, butynyl,pentyn-2-yl etc.; C₃₋₅ alkynyl may also be understood in a similarmanner. C₃₋₅ alkynyl is preferred.

The term “halogen” refers to fluorine, chlorine, bromine, and iodineatom.

The term “C₃₋₈ cyclyl” in “C₃₋₈ cyclylalkoxy”, “C₃₋₈ cyclylalkylamino”refers to a saturated or unsaturated carbon ring group having 3-8 carbonatoms. In one embodiment of the invention, C₃₋₈ cyclyl refers to C₃₋₈cycloalkyl.

The term “heterocycyl” or “heterocyclyl” refers to one or more5-membered, 6-membered or 7-membered carbon cyclic systems, including afused cyclic system having 4-10 atoms, wherein the cyclic systemcontains at least one and at most four heteroatoms selected fromnitrogen, oxygen or sulphur, provided that the ring of the group doesnot contain two contiguous O or S atoms. A fused cyclic system may be aheterocycle fused to an aromatic group. The preferred heterocycylincludes, but is not limited to, pyrrolidinyl, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothienyl, piperidyl, morpholinyl ring,cyclohexyl ring, piperazine ring, etc., which may be substituted withthe following groups: C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano, halogen, hydroxyl,amino, nitro, mono(C₁₋₆)alkylamino, di(C₁₋₆)alkylamino, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy. Preferably, theheterocyclyl is a 3- to 8-membered heterocyclyl, more preferably a 5- to8-membered heterocyclyl.

The term “heterocyclylalkyl” refers to C₁₋₆ alkyl (as defined above)substituted with heterocyclyl (as defined above). 3- to 8-memberedheterocyclylalkyl or 3- to 5-membered heterocyclylalkyl is preferred.More preferred heterocyclylalkyl is 5-membered or 6-memberedheterocyclyl-C₁₋₃-alkyl. The example includes tetrahydropyranylmethyl.

The term “heterocyclylalkylamino” refers to heterocyclyl (as definedabove) substituted with aminoalkyl (as defined above) (e.g. C₁₋₆aminoalkyl or C₁₋₄ aminoalkyl or C₁₋₃ aminoalkyl). 3- to 8-memberedheterocyclylalkylamino or 3- to 5-membered heterocyclylalkylamino arepreferred.

The term “heterocyclylalkoxy” refers to heterocyclyl (as defined above)substituted with alkoxy (as defined above) (e.g. C₁₋₆alkoxy orC₁₋₄alkoxy or C₁₋₃alkoxy). 3- to 8-membered heterocyclylalkoxy or 3- to5-membered heterocyclylalkoxy are preferred.

The term “cycloalkylalkyl” refers to C₁₋₆ alkyl (as defined above)substituted with C₃₋₈ cycloalkyl (as defined above). More preferredheterocyclyl is 5-membered or 6-membered cycloalkyl-C₁₋₃-alkyl. Theexample includes cyclopropylmethyl.

Advantageous Effects of the Invention

The compounds according to the invention have strong inhibitory activity(at nM level) against wild-type and various drug-resistant HIV viralstrains and exhibit good druggability. The novel compounds according tothe invention have high efficiency, low toxicity, good solubility, logPvalue (<5) and metabolic stability (t_(1/2)), all of which facilitatethe absorption of the drug in vivo and generation of a better effect.The compounds according to the invention are potential to be anti-HIVdrugs.

SPECIFIC MODES FOR CARRYING OUT THE INVENTION

The embodiments of the invention are described by combining thefollowing examples. However, a person skilled in the art understandsthat the following examples are only intended to describe the invention,and should not be regarded as defining the scope of the invention. Inthe case where the concrete conditions are not indicated in theexamples, the examples are carried out according to conventionalconditions or the conditions recommended by the manufacturer. Thereagents or apparatuses, the manufacturers of which are not indicated,are the conventional products that are commercially available.

Firstly, according to the following preparation examples 1-3, nitrotarget compound is prepared, and then is reduced to obtain the aminotarget compound. The scheme is as follows:

PREPARATION EXAMPLE 1 Preparation of5-chloro-N-(4-cyanophenyl)-2-nitro-4-substituent (R) aniline(Intermediate I) or 6-chloro-3-nitro-2-(4-cyanoanilinyl)pyridine(Intermediate II)

Method A. 2, 4-dichloro-5-substituent nitrobenzene (1 equiv) and4-cyanoaniline (1.1 equiv) were dissolved in DMF (3 ml), and under thecondition of ice bath, potassium t-butoxide was added in batches, andthe resultant solution was stirred for about 1 h at room temperature.The reaction solution was poured into ice-water, the pH was adjusted toabout 6 with 5% aqueous hydrochloric acid solution, and yellowprecipitates formed. The mixture was filtered, washed with water untilit was neutral, dried, and isolated and purified through medium pressurecolumn, to get pure intermediate I.

Method B. 2,6-dichloro-3-nitropyridine (10 mmol) and 4-cyanoaniline (12mmol) were placed in a reaction bottle; the reaction took place innitrogen atmosphere at 140° C. for 4 h. The reaction solution was pouredinto ice-water, pH was adjusted to 2-3, yellow solid was precipitated,filtered, washed with water, and dried to get a crude product. 95%ethanol was used to recrystallize it to get the correspondingintermediate II, with a yield of 73%, mp 175-8° C.

PREPARATION EXAMPLE 2 Preparation ofN¹-(4′-cyanophenyl)-5-(4″-substituted-2″,6″-dimethylphenoxy)-4-substituent-2-nitroaniline(IV)

Method A: intermediate I or intermediate II (1 equiv) and4-substituent-2,6-dimethylphenol (1.2 equiv) were dissolved in DMF (2-5ml), and anhydrous potassium carbonate (2 equiv) or cesium carbonate wasadded; the reaction lasted for 15 min at 190° C. under microwave. Thereaction solution was poured into a suitable amount of ice-water; pH wasadjusted to be neutral with 5% hydrochloric acid solution; the resultantsolution was extracted with ethyl acetate for three times; the organicphase was dried with anhydrous sodium sulfate and was dried underrotation to get the crude product of the correspondingdiarylnitrobenzene intermediate IV or diarylnitropyridine intermediateV. The crude product was isolated and purified through medium pressurecolumn (petroleum ether/dichloromethane).

Method B: said reactants and reagents were reacted in an oil-bath at130° C. for about 5 h, and the post-treatment was carried out asdescribed above. Intermediate IV or intermediate V was obtained.

Method C: 266 mg (1.5 mmol) of (EtO)₂P(O)CH₂CN was dissolved in 15 mL ofTHF, cooled in an ice-water bath, and stirred; 168 mg (1.5 mmol) oft-BuOK was added, and the resultant solution was stirred for 30 min. Thereaction solution was transferred at room temperature and was furtherstirred for 30 min. 1 mmol of formyl-containing intermediate V wasdissolved in 15 mL of THF, and the resultant solution was added dropwiseto said reaction bottle at room temperature. After stirring for 2-6 h,the reaction was stopped. The reaction solution was poured into 100 mLof water, stirred, and extracted with ethyl acetate (50 mL×3). Theorganic phase was dried over anhydrous sodium sulfate, concentrated, andisolated through a flash preparative column chromatography to get thecorresponding product (intermediate IV or intermediate V) (eluent:dichloromethane/petroleum ether=0-100%, 200-300 mush silica gel).

PREPARATION EXAMPLE 3 The Reduction Method for Preparation ofDiarylanilines or Diarylpyridinamines

Method A (catalytic hydrogenation): diaryl nitrobenzene or diarylnitropyridine (1 mmol) was placed in anhydrous ethanol (30 mL), anexcessive amount of Pd/C (5%) was added, and the resultant mixture wasshaked for about 2 h (or until no hydrogen gas was absorbed) at apressure of 30-40 p.s.i. after hydrogen gas was introduced, and then thereaction was stopped. The resultant mixture was filtered to remove thecatalyst, and the filtrate was washed with ethanol for several times,and the crude product obtained after concentrating of the filtrate wasisolated through a column chromatography (eluent is MeOH/CH₂Cl₂), to getthe corresponding diarylaniline or diarylpyridinamine compound.

Method B (selective reduction reaction): to a mixed solution of diarylnitrobenzene or diaryl nitropyridine (1 mmol) in THF and water (30 mL,v/v 1:1), a small amount of aqueous ammonia (25%) was added, and an10-fold amount of sodium hydrosulfite was added in batches to thereaction bottle. The reaction finished after stirring the reactionsolution at room temperature for about 2 h. The reaction solution waspoured into ice-water, extracted with ethyl acetate, and isolated; theorganic solvent was removed, and the crude product was isolated througha chromatographic column (eluent is MeOH/CH₂Cl₂) to get thecorresponding diarylaniline or diarylpyridinamine compound as desired.

EXAMPLE 1 Preparation of5-(4″-cyanovinyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-trifluoromethyl-2-nitroaniline(Compound 1)

4-cyano aniline (130 mg, 1.1 mmol) and2,4-dichloro-5-nitrobenzotrifluoride (260 mg, 1 mmol) were used asstarting materials. A general synthetic method of intermediate I wasemployed to get5-chloro-N-(4-cyanophenyl)-2-nitro-4-trifluoromethylaniline (I-1) (281mg) with a yield of 82%, as a yellow solid, and with a melting point of180-182° C.; MS m/z (%) 359.2 (M+NH₄, 100). I-1 and4″-formyl-2″,6″-dimethylphenol were coupled by Method A in PreparationExample 2. The product was dissolved in 15 mL of THF, and was reactedwith (EtO)₂P(O)CH₂CN (1.5 mmol) and an equivalent mole of potassiumt-butoxide in THF by Method C in Preparation Example 2 under stirringfor about 3 h. The product obtained by conventional post-treatment wasisolated and purified through medium pressure column(dichloromethane/methanol) to get Compound 1, with a melting point of248-250° C. and a yield of 87%. ¹H NMR δ ppm 2.15 (6H, s, 2×CH₃), 5.85(1H, d, J=16.4 Hz, ═CH), 6.27 (1H, s, ArH-6), 7.10 (2H, d, J=8.8 Hz,ArH-2′,6′), 7.21 (2H, s, ArH-3″,5″), 7.32 (1H, d, J=16.4 Hz, CH═), 7.52(2H, d, J=8.8 Hz, ArH-3′,5′), 8.67 (1H, s, ArH-3), 9.91 (1H, s, NH); MSm/z (%) 501.1 (M+Na, 100).

EXAMPLE 2 Preparation of5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-trifluoromethyl-1,2-phenylenediamine(Compound 2)

Compound 1 was subjected to catalytic hydrogenation with 5-10% Pd/C inanhydrous ethanol at a pressure of 30-80 p.s.i. (Method A in PreparationExample 3). After reaction for about 2 h, Pd/C was filtered out, thesolvent was removed under reduced pressure, and purification was carriedout through medium pressure column (dichloromethane/methanol, gradientelution) to get Compound 1 with a yield of 31% as a brown solid. ¹H NMR(CDCl₃) δ ppm 2.11 (6H, s, 2×CH₃), 2.61 (2H, t, J=7.2 Hz, CH₂CN), 2.87(2H, t, J=7.2 Hz, ArCH₂), 5.72 (1H, s, NH), 6.20 (1H, s, ArH-6), 6.64(2H, d, J=8.8 Hz, ArH-2′,6′), 6.94 (2H, s, ArH-3″,5″), 7.14 (1H, s,ArH-3), 7.44 (2H, d, J=8.8 Hz, ArH-3′,5′); MS m/z (%) 451.1 (M+1, 100).

EXAMPLE 3 Preparation of5-(4″-cyanovinyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-methoxycarbonyl-2-nitroaniline(Compound 3)

4-cyano aniline and 2,4-dichloro-5-methoxycarbonyl-nitrobenzene asstarting materials were coupled by Method A in Preparation Example 1 toget intermediateI-2[4-chloro-N²-(4′-cyanophenyl)-5-methoxycarbonyl-nitrobenzene]. I-2was coupled with 2,6-dimethyl-4-formylphenol by Method A in PreparationExample 2, and was subjected to acrylcyanidation (Method C) to getCompound 3; with a yield of 88%; yellow solid; m.p. 260-262° C. ¹H NMR δppm 2.16 (6H, s, 2×CH₃), 3.96 (3H, s, OCH₃), 5.84 (1H, d, J=16.4 Hz,═CH), 6.26 (1H, s, ArH-6), 7.08 (2H, d, J=8.8 Hz, ArH-2′,6′), 7.20 (2H,s, ArH-3″,5″), 7.32 (1H, d, J=16.4 Hz, CH═), 7.50 (2H, d, J=8.8 Hz,ArH-3′,5′), 9.00 (1H, s, ArH-3), 9.87 (1H, s, NH); MS m/z (%) 469.4(M+1, 100).

EXAMPLE 4 Preparation of5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-methoxycarbonyl-1,2-phenylenediamine(Compound 4)

Compound 3 was subjected to catalytic hydrogenation (Method A inPreparation Example 3) to get Compound 4 as a off-white solid (a yieldof 47%), with a melting point of 236-238° C. ¹H NMR δ ppm 2.13 (6H, s,2×CH₃-2″,6″), 2.61 (2H, t, —CH₂—), 2.87 (2H, t, Ar—CH₂—), 3.93 (3H, s,—COOCH₃), 5.90 (1H, s, NH), 6.23 (1H, s, ArH-6), 6.69 (2H, d, J=8.8 Hz,ArH-2′,6′), 6.93 (2H, s, ArH-3″,5″), 7.43 (2H, d, J=8.8 Hz, ArH-3′,5′),7.45 (1H, s, ArH-3). MS m/z (%) 409.2 (M+1, 100).

EXAMPLE 5 Preparation ofN¹-(4′-cyanophenyl)-5-(4″-cyanovinyl-2″,6″-dimethylphenoxy)-4-hydroxymethyl-2-nitroaniline(Compound 5)

The ester group of Compound 3 was reacted with lithium borohydride(LiBH₄) in a mixed solvent of THF and methanol for 1 h, and was reducedto hydroxymethyl to get Compound 5, with a yield of 91%; yellow solid;m.p. 232-234° C.; ¹H NMR δ ppm 2.15 (6H, s, 2×CH₃), 4.89 (2H, s, OCH₂),5.85 (1H, d, J=16.4 Hz, ═CH), 6.27 (1H, s, ArH-6), 7.05 (2H, d, J=8.8Hz, ArH-2′,6′), 7.21 (2H, s, ArH-3″,5″), 7.28 (1H, d, J=16.4 Hz, CH═),7.47 (2H, d, J=8.8 Hz, ArH-3′,5′), 8.41 (1H, s, ArH-3), 9.70 (1H, s,NH); MS m/z (%) 439.3 (M−1, 100).

EXAMPLE 6 Preparation of5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-hydroxymethyl-1,2-phenylenediamine(Compound 6)

Compound 5 (440 mg, 1 mmol) was subjected to catalytic hydrogenation(Method A in Preparation Example 3) to get Compound 6 (264 mg), with ayield of 64%; off-white solid; with a melting point of 115-117° C.; ¹HNMR (CDCl₃) δ ppm 2.10 (6H, s, 2×CH₃), 2.61 (2H, t, J=7.2 Hz, CH₂CN),2.87 (2H, t, J=7.2 Hz, ArCH₂), 4.86 (2H, s, CH₂O), 5.54 (1H, s, NH),6.04 (1H, s, ArH-6), 6.55 (2H, d, J=8.8 Hz, ArH-2′,6′), 6.91 (1H, s,ArH-3), 6.93 (2H, s, ArH-3″,5″), 7.40 (2H, d, J=8.8 Hz, ArH-3′,5′); MSm/z (%) 413.4 (M+1, 100).

EXAMPLE 7 Preparation of4-carboxyl-5-(4″-cyanovinyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-2-nitroaniline(Compound 7)

In the presence of aqueous NaOH solution (10%), Compound 3 was reactedin a mixed solvent of methanol and THF at room temperature for 4 h toget Compound 7 (454 mg, 1 mmol), with a yield of 90%; m.p. 262-265° C.;¹H NMR (DMSO-d₆) δ ppm 2.06 (6H, s, 2×CH₃), 5.95 (1H, s, ArH-6), 6.44(1H, d, J=16.4 Hz, ═CH), 7.22 (2H, d, J=8.8 Hz, ArH-2′,6′), 7.47 (2H, s,ArH-3″,5″), 7.58 (1H, d, J=16.4 Hz, CH═), 7.65 (2H, d, J=8.8 Hz,ArH-2′,6′), 8.72 (1H, s, ArH-3), 9.79(1H, s, NH), 13.21 (1H, s, COOH);MS m/z (%) 453.4 (M−1, 100).

EXAMPLE 8 Preparation of4-carboxyl-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-1,2-phenylenediamine(Compound 8)

Compound 7 was subjected to catalytic hydrogenation (Method A inPreparation Example 3) to get Compound 8, with a yield of 33.1%;off-white solid; ¹H NMR (CDCl₃) δ ppm 2.16 (6H, s, 2×CH₃), 2.64 (2H, t,J=7.2 Hz, CH₂CN), 2.91 (2H, t, J=7.2 Hz, ArCH₂), 6.08 (1H, s, NH), 6.31(1H, s, ArH-6), 6.76 (2H, d, J=8.8 Hz, ArH-2′,6′), 7.01 (2H, s,ArH-3″,5″), 7.46 (2H, d, J=8.8 Hz, ArH-3′,5′), 7.73 (1H, s, ArH-3); MSm/z (%) 425.2 (M−1, 100).

EXAMPLE 9 Preparation ofN¹-(4′-cyanophenyl)-5-(4″-cyanovinyl-2″,6″-dimethylphenoxy)-4-acylamino-2-nitroaniline(Compound 9)

Compound 7 and SOCl₂ (0.5 mL) were stirred in anhydrous THF for amoment, aqueous ammonia (25-30%, 1 mL) was added in the condition of anice bath. The resultant solution was stirred for 30 min, and poured intoice-water to precipitate a solid. The mixture was filtered and isolatedthrough column chromatography to get Compound 9, with a yield of 87%;yellow solid; m.p. 278-280° C.; ¹H NMR δ ppm 2.16 (6H, s, 2×CH₃), 5.88(1H, d, J=16.4 Hz, ═CH), 6.29 (1H, s, ArH-6), 7.08 (2H, d, J=8.8 Hz,ArH-2′,6′), 7.24 (2H, s, ArH-3″,5″), 7.33 (1H, d, J=16.4 Hz, CH═), 7.50(2H, d, J=8.8 Hz, ArH-3′,5′), 9.30 (1H, s, ArH-3), 9.82 (1H, s, NH); MSm/z (%) 454.3 (M+1, 100).

EXAMPLE 10 Preparation of4-carbamoyl-N¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-1,2-phenylenediamine(Compound 10)

Compound 9 (453 mg, 1 mmol) was subjected to catalytic hydrogenation(Method A in Preparation Example 3) to get Compound 10 (357 mg), with ayield of 84%; off-white solid; m.p. 274-276° C.; ¹H NMR (CDCl₃) δ ppm2.14 (6H, s, 2×CH₃), 2.63 (2H, t, J=7.2 Hz, CH₂CN), 2.89 (2H, t, J=7.2Hz, ArCH₂), 5.90 (1H, s, NH), 6.23 (1H, s, ArH-6), 6.70 (2H, d, J=8.8Hz, ArH-2′,6′), 6.99 (2H, s, ArH-3″,5″), 7.43 (2H, d, J=8.8 Hz,ArH-3′,5′), 7.79 (1H, s, ArH-3), 5.93, 7.85 (—CONH₂); MS m/z (%) 426.4(M+1, 100).

EXAMPLE 11 Preparation ofN¹-(4′-cyanophenyl)-5-(4″-cyanovinyl-2″,6″-dimethylphenoxy)-4-(N-methylacylamino)-2-nitroaniline(Compound 11)

Compound 7 and SOCl₂ (0.5 mL) were stirred in anhydrous THF for amoment, aqueous methylamine (25-30%, 1 mL) was added in the condition ofan ice bath. The resultant solution was stirred for 30 min, and pouredinto ice-water to precipitate a solid. The mixture was filtered andisolated through silica gel column chromatography to get Compound 11,with a yield of 60%; yellow solid; m.p. 218-220° C.; ¹H NMR δ ppm 2.17(6H, s, 2×CH₃), 3.08 (3H, d, CH₃), 5.88 (1H, d, J=16.4Hz, ═CH), 6.28(1H, s, ArH-6), 7.07 (2H, d, J=8.8 Hz, ArH-2′,6′), 7.25 (2H, s,ArH-3″,5″), 7.34 (1H, d, J=16.4Hz, CH═), 7.49 (2H, d, J=8.8 Hz,ArH-2′,6′), 7.50 (1H, NMe), 9.29 (1H, s, ArH-3), 9.78 (1H, s, NH); MSm/z (%) 468.3 (M+1, 100).

EXAMPLE 12 Preparation of5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-(N-methyl-carbamoyl)-1,2-phenylenediamine(Compound 12)

Compound 11 (467 mg, 1 mmol) was subjected to catalytic hydrogenation(Method A in Preparation Example 3) to get Compound 12 (289 mg), with ayield of 66%; off-white solid; m.p. 110-112° C.; ¹H NMR (CDCl₃) δ ppm2.10 (6H, s, 2×CH₃), 2.63 (2H, t, J=7.2 Hz, CH₂CN), 2.89 (2H, t, J=7.2Hz, ArCH₂), 3.06 (3H, d, J=4.8 Hz, OCH₃), 5.85 (1H, s, NH), 6.21 (1H, s,ArH-6), 6.67 (2H, d, J=8.8 Hz, ArH-2′,6′), 6.98 (2H, s, ArH-3″,5″), 7.42(2H, d, J=8.8 Hz, ArH-3′,5′), 7.82 (1H, s, ArH-3), 7.97 (1H, d, J=4.8Hz, CONH); MS m/z (%) 440.4 (M+1, 100).

EXAMPLE 13 Preparation ofN-(4′-cyanophenyl)-5-(4″-cyanovinyl-2″,6″-dimethylphenoxy)-4-aminosulfonyl-2-nitroaniline(Compound 13)

4-cyano aniline and 2,4-dichloro-5-aminosulfonyl-nitrobenzene asstarting materials were coupled by Method A in Preparation Example 1 toget 4-chloro-N²-(4′-cyanophenyl)-5-aminosulfonyl-nitrobenzene(intermediate I-3). I-3 and 2,6-dimethyl-4-formylphenol were coupled byMethod A in Preparation Example 2, and were subjected toacrylcyanidation (Method C) to get Compound 13, with a yield of 45%;yellow solid; m.p. 198-200° C.; ¹H NMR (DMSO-d₆) δ ppm 2.16 (6H, s,2×CH₃), 6.38 (1H, d, J=16.4 Hz, ═CH), 6.54 (1H, s, ArH-6), 7.32 (2H, s,ArH-3″,5″), 7.51 (2H, d, J=8.8 Hz, ArH-2′,6′), 7.52 (1H, d, J=16.4 Hz,═CHCN), 7.85 (2H, d, J=8.8 Hz, ArH-3′,5′), 8.25 (1H, s, ArH-3), 9.79(1H, s, NH); MS m/z (%) 488 (M−1, 100).

EXAMPLE 14 Preparation of 5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4‘-cyanophenyl)-4-aminosulfonyl-1,2-phenylenediamine (Compound 14)

Compound 13 (489 mg, 1 mmol) was subjected to catalytic hydrogenation(Method A in Preparation Example 3) to get Compound 14 (261 mg), with ayield of 57%; off-white solid; m.p. 140-142° C.; ¹H NMR (CDCl₃) δ ppm2.13 (6H, s, 2×CH₃), 2.64 (2H, t, J=6.8 Hz, CH₂), 2.86 (2H, t, J=6.8 Hz,ArCH₂), 6.14 (1H, s, NH), 6.33 (1H, s, ArH-6), 6.88 (1H, s, ArH-3), 6.93(2H, s, ArH-3″,5″), 7.06 (2H, d, J=8.8 Hz, ArH-2′,6′), 7.57 (2H, d,J=8.8 Hz, ArH-3′,5′); MS m/z (%) 460.2 (M−1, 100).

EXAMPLE 15 Preparation of6-(2,6-dimethyl-4-allyl-phenoxy)-2-(4-cyanoanilinyl)-3-nitropyridine(Compound 15)

4-cyano aniline was coupled with 2,6-dichloro-3-nitropyridine by MethodB in Preparation Example 1 to prepare6-chloro-N²-(4′-cyanobenzene)-3-nitropyridine (intermediate II-1), whichwas coupled with 2,6-dimethyl-4-allylphenol by Method B in Preparation 2to get Compound 15.

EXAMPLE 16 Preparation ofN²-(4-cyanoanilinyl)-6-(2,6-dimethyl-4-propylphenoxy)-3-aminopyridine(Compound 16)

Compound 15 (402 mg, 1 mmol) was subjected to catalytic hydrogenation(Method A in Preparation Example 3) to get Compound 16 (140 mg), with ayield of 38%; gray solid. ¹H NMR (DMSO-d) δ ppm 0.92 (3H, t, J=7.6 Hz,—CH₃), 1.65 (2H, m, CH₂), 2.01 (6H, s, ArCH₃×2), 2.55 (2H, m, ArCH₂),4.75 (2H, s, NH₂), 6.37 (1H, d, J=8.0 Hz, ArH-5), 6.97 (2H, s,ArH-3″,5″), 7.11 (1H, d, J=8.0 Hz, ArH-4), 7.29 (2H, d, J=8.8 Hz,ArH-2′,6′), 7.38 (2H, d, ArH-3′,5′), 8.30 (1H, s, NH); MS m/z (%) 378(M+1, 100).

EXAMPLE 17 Preparation ofN-(4′-cyanophenyl)-5-(4″-hydroxymethyl-2″,6″-dimethylphenoxy)-4-hydroxymethyl-2-nitroaniline(Compound 17)

Intermediate I-1 and 4″-formyl-2″,6″-dimethylphenol were coupled byMethod A in Preparation Example 2, and the product thus obtained wasreacted with lithium borohydride in a mixed solvent of THF and methanol,at room temperature under stirring for 1 h, to get the reductantproduct, i.e. intermediate compound 17, with a yield of 85%; yellowsolid; m.p. 216-218° C.; ¹H NMR δ ppm 2.13 (6H, s, 2×CH₃), 4.66 and 4.88(each 2H, d, CH₂O), 6.28 (1H, s, ArH-6), 7.03 (2H, d, J=8.8 Hz,ArH-2′,6′), 7.12 (2H, s, ArH-3″,5″), 7.47 (2H, d, J=8.8 Hz, ArH-3′,5′),8.38 (1H, s, ArH-3), 9.70 (1H, s, NH); MS m/z (%) 442.4 (M+Na, 100).

EXAMPLE 18 Preparation ofN¹-(4′-cyanophenyl)-5-(4″-hydroxymethyl-2″,6″-dimethylphenoxy)-4-hydroxymethyl-1,2-phenylenediamine(Compound 18)

Compound 17 (419 mg, 1 mmol) was subjected to catalytic hydrogenation(Method A in Preparation Example 3) to get Compound 18 (239 mg), with ayield of 62%; off-white solid; ¹H NMR (CDCl₃) δ ppm 2.12 (6H, s, 2×CH₃),3.52 (2H, s, NH₂), 4.63 and 4.87 (each 2H, s, ArCH₂O), 5.48 (1H, s, NH),6.06 (1H, s, ArH-6), 6.54 (2H, d, J=8.8 Hz, ArH-2′,6′), 6.92 (1H, s,ArH-3), 7.08 (2H, s, ArH-3″,5″), 7.39 (2H, d, J=8.8 Hz, ArH-3′,5′); MSm/z (%) 390.3 (M+1, 100).

EXAMPLE 19 Preparation ofN-(4′-cyanophenyl)-5-(4″-cyano-2″,6″-dimethylphenoxy)-4-hydroxymethyl-2-nitroaniline(Compound 19)

Intermediate I-2 was coupled to 4″-cyano-2″,6″-dimethylphenol by MethodA in Preparation Example 2, wherein the ester group on the intermediatering was reduced with LiBH₄ (the method is the same as the one inExample 3) to get Compound 19.

EXAMPLE 20 Preparation ofN²-(4-cyanoanilinyl)-6-(2,6-difluoro-4-cyanovinyl)phenoxy-3-nitropyridine(Compound 20)

Intermediate II-1 and 2,6-difluoro-4-formylphenol were coupled by MethodB in Preparation Example 2, followed by coupling by Method A inPreparation Example 2, and acrylcyanidation (Method C) to get Compound20.

EXAMPLE 21 Preparation ofN²-(4-cyanoanilinyl)-6-(2,6-difluoro-4-cyanoethyl-phenoxy)-3-aminopyridine(Compound 21)

Compound 20 (396 mg, 1 mmol) was subjected to catalytic hydrogenation(Method A in Preparation Example 3) to get Compound 21 (198 mg), with ayield of 52%; gray solid; ¹H NMR (DMSO-d₆) δ ppm: 3.00-2.88 (4H, m,ArCH₂CH₂CN) 4.91 (2H, s, NH₂), 6.55 (1H, d, J=8.4 Hz, ArH-5), 7.15 (1H,d, J=8.4 Hz, ArH-4), 7.35 (2H, d, J=8.8 Hz, ArH-2′,6′), 7.39 (2H, d,J=8.4 Hz, ArH-3″,5″), 7.40 (2H, d, J=8.8 Hz, ArH-3′,5′), 8.39 (1H, s,NH); MS m/z (%) 390 (M−1, 100).

EXAMPLE 22 Preparation of 6-(2,6-difluoro-4-methylacrylate)phenoxy-2-(4-cyanoanilinyl)-3-nitropyridine (Compound 22)

Intermediate II-1 and 2,6-difluoro-4-formylphenol were coupled by MethodA in Preparation Example 2; the product and Ph₃PCHCOOMe were refluxed inchloroform overnight under the protection of nitrogen gas. The reactionsolution was concentrated and was purified by column chromatography toget Compound 22.

EXAMPLE 23 Preparation of N²-(4-cyanoanilinyl)-6-(2,6-difluoro-4-methylpropionate phenoxy)-3-aminopyridine (Compound 23)

Compound 22 (452 mg, 1 mmol) was subjected to catalytic hydrogenation(Method A in Preparation Example 3) to get Compound 23 (158 mg), with ayield of 40%; gray solid; m.p. 209-211° C.; ¹H NMR (DMSO-d₆) δ ppm: 2.72(2H, t, J=7.6 Hz, CH₂CO), 2.93 (2H, t, J=7.6 Hz, ArCH₂), 3.60 (3H, s,OCH₃), 4.90 (2H, s, NH₂), 6.54(1H, d, J=8.4 Hz, ArH-5), 7.15 (1H, d,J=8.4 Hz, ArH-4), 7.21 (2H, d, J=9.2 Hz, ArH-3″,5″), 7.39-7.34 (4H, m,ArH-2′,3′,5′,6′), 8.39 (1H, s, NH); MS m/z (%) 423 (M−1, 100).

EXAMPLE 24 Preparation ofN²-(4-cyanoanilinyl)-6-(2,6-difluoro-4-(3-hydroxypropyl)phenoxy)-3-aminopyridine(Compound 24)

Compound 22 (452 mg, 1 mmol) was dissolved in the mixture of 15 mL ofTHF and 15 mL of ethanol, an excessive amount of Pd/C(10%) was added,and the resultant mixture was subjected to catalytic hydrogenation(Method A in Preparation Example 3) at a pressure of 15 Psi for 6 h.Pd/C solid was filtered out, the filtrate was cooled in an ice-waterbath, and 280 mg (10 mmol) of LiBH₄ was added in batches. After stirringfor 30 min, the reaction finished. The reaction solution was poured into50 mL of ice-water, the pH was adjusted to 4-5 with 1 mol/L HCl, and thereaction solution was extracted with ethyl acetate, and dried withanhydrous sodium sulfate. After removing the solvent, the residue wasisolated by column chromatography to get Compound 24 (264 mg), with ayield of 67%; gray solid; ¹H NMR (DMSO-d₆) δ ppm: 1.76 (2H, m, CH₂),2.70 (2H, t, J=2.8 Hz, CH₂O), 3.43 (2H, t, J=2.0 Hz, ArCH₂), 4.52 (1H,br s, OH), 4.90 (2H, br s, NH₂), 6.54 (1H, d, J=8.4 Hz, ArH-5), 7.15(3H, d, J=8.4 Hz, ArH-4,3″,5″), 7.36 (4H, s, ArH-2′,3′,5′,6′), 8.40 (1H,s, NH); MS m/z (%) 395 (M−1, 100).

EXAMPLE 25 Preparation of6-(2-bromo-((E)-4-cyanovinyl)-5-methoxyphenoxy)-2-(4-cyanoanilinyl)-3-nitropyridine(Compound 25)

Intermediate II-1 and 2-bromo-6-methoxy-4-formylphenol were coupled byMethod A in Preparation Example 2, the product thus obtained was reactedwith (EtO)₂P(O)CH₂CN by Method C in Preparation Example 2 to getCompound 25.

EXAMPLE 26 Preparation of6-(2-bromo-4-cyanoethyl-5-methoxy)phenoxy-2-(4-cyanoanilinyl)-3-aminopyridine(Compound 26A) and6-(2-bromo-4-cyanovinyl-5-methoxy)phenoxy-2-(4-cyanoanilinyl)-3-aminopyridine(Compound 26B)

Compound 25 (492 mg) was reduced by catalytic hydrogenation (Method A inPreparation Example 3), under stirring at room temperature for 2 h.After conventional post-treatment and isolation by columnchromatography, Compound 26A (285 mg) was obtained with a yield of 61%;gray solid; m.p. 242-244° C.; ¹H-NMR δ ppm 8.35 (1H, s, NH), 7.69 (1H,d, J=16.4 Hz, ArH—CH═CH), 7.65 (1H, s, ArH-5″), 7.55 (1H, s, ArH-3″),7.31 (4H, s, ArH-2′,3′,5′,6′), 7.13 (1H, d, J=8.0 Hz, ArH-4), 6.68 (1H,d, J=8.0 Hz, ArH-5), 4.83 (2H, s, NH₂), 3.75 (3H, s, ArOCH₃), 3.00-2.88(4H, m, ArCH₂CH₂CN); MS m/z 462 [M−1, 100].

Compound 25 (492 mg) was selectively reduced with sodium hydrosulfite(Method B in Preparation Example 3) to get 285 mg of Compound 26B, witha yield of 61%; white solid; 219-220° C.; ¹H NMR δ ppm 8.35 (1H, s, NH),7.69 (1H, d, J=16.4 Hz, ArCH═), 7.65 (1H, s, ArH-3″), 7.55 (1H, s,ArH-5″), 7.31 (4H, br s, ArH-2′,3′,5′,6′), 7.13 (1H, d, J=8.8 Hz,PyH-4), 6.68 (1H, d, J=16.4 Hz, ═CHCN), 6.48 (1H, d, J=8.8 Hz, PyH-5),4.83 (2H, s, NH₂), 3.75 (3H, s, OCH₃); MS m/z (%) 460.3 (M−1, 100),462.1 (M+1, 60).

EXAMPLE 27 Preparation of3-nitro-6-(2,6-dibromo-4-((E)-cyanovinyl)phenoxy)-2-(4-cyanoanilinyl)pyridine(Compound 27)

Intermediate II-1 and 2,6-dibromo-4-formylphenol were coupled by methodin Preparation Example 2, and the product was subjected toacrylcyanidation according to Method C in Preparation Example 2 to getCompound 27.

EXAMPLE 28 Preparation of2-(4-cyanoanilinyl)-6-(2,6-dibromo-4-cyanoethyl)phenoxy)-3-aminopyridine(Compound 28)

Compound 27 (541 mg) was subjected to catalytic hydrogenation reduction(Method A in Preparation Example 3) to get Compound 28 (200 mg), with ayield of 43%; gray solid; m.p. 231-233° C.; ¹H NMR δ ppm: 8.39 (1H, s,NH), 8.15 (2H, s, ArH-3″,5″), 7.31-7.29 (4H, m, ArH-2′,3′,5′,6′), 7.16(1H, d, J=8.0 Hz, ArH-4), 6.56 (1H, d, J=8.0 Hz, ArH-5), 4.90 (2H, s,NH₂), 3.00-2.88 (4H, m, ArCH₂CH₂CN); MS m/z 512 [M−1, 100].

EXAMPLE 29 Preparation ofN²-(4-cyanoanilinyl)-6-(2,6-difluoro-4-((E)-1-methyleneacetonyl)phenoxy)-3-nitropyridine(Compound 29)

Intermediate II-1 and 2,6-difluoro-4-formylphenol were coupled by MethodA in Preparation Example 2; the resultant product and acetone werestirred in aqueous NaOH solution (10%, 2 mL) at room temperature for 1h, and were poured into water. The pH was adjusted to be acidic toprecipitate a solid. The mixture was filtered, washed, dried, andisolated by flash preparative chromatography to get Compound 29; yellowsolid; m.p. 275-277° C.

EXAMPLE 30 Preparation ofN²-(4-cyanoanilinyl)-6-(2,6-difluoro-4-(2-butanonyl)phenoxy)-3-aminopyridine(Compound 30)

Compound 29 (436 mg) was subjected to catalytic hydrogenation (Method Ain Preparation Example 3) to get Compound 30 as the reduction product(167 mg), with a yield of 43%; grey solid; m.p. 142-144° C., ¹H NMR δppm: 8.42 (1H, s, NH), 7.40 (2H, d, J=8.8 Hz, ArH-3′,5′), 7.35 (2H, d,J=8.8 Hz, ArH-2′,6′), 7.19-7.14 (3H, m, ArH-4, 3″,5″), 6.55 (1H, d,J=8.0 Hz, ArH-5), 4.92 (2H, s, NH₂), 2.87-2.81 (4H, m, ArCH₂CH₂CO), 2.14(3H, s, ArCH₂CH₂COCH₃); MS m/z 407 [M−1, 100].

EXAMPLE 31 Preparation ofN-(4′-cyanophenyl)-5-(4″-cyano-2″,6″-dimethylphenoxy)-4-chloromethyl-2-nitroaniline(Compound 31)

Dichloromethane solution of Compound 19 was added dropwise at roomtemperature to DMF solution of cyanuric chloride, and the temperaturewas increased to 70-80° C. After stirring for about 1-2 h, the resultantsolution was poured into ice-water, extracted with ethyl acetate, dried,filtered, concentrated, isolated and purified to get Compound 31.

EXAMPLE 32 Preparation ofN-(4′-cyanophenyl)-5-(4″-cyanovinyl-2″,6″-dimethylphenoxy)-4-[(2-methoxyethoxyl)methyl]-2-nitroaniline(Compound 32)

Compound 5 (105 mg, 0.24 mmol), 2-methoxy bromoethane (50 mg, 0.36mmol), K₂CO₃ (104 mg, 0.75 mmol) and DMF (5 mL) were added to a 3-neckflask in an oil bath and heated at 70° C. for 6 h until the reactionfinished. The reaction solution was poured into ice-water, the pH wasadjusted to neutral, and a yellow solid was precipitated. Afterstanding, filtration, and drying, the residue was isolated through PTLC(CH₂Cl₂:CH₃OH 200:1) to get a tawny solid (52 mg), with a yield of 44%.¹H NMR δ ppm 8.29 (1H, s, ArH-3), 7.38 (2H, d, J=8.0 Hz, ArH-3′,5′),7.33 (2H, d, J=16.0 Hz, CH═), 7.23 (2H, s, ArH-3″,5″), 6.48 (1H, s,ArH-6), 6.44 (2H, d, J=8.0 Hz, ArH-2′,6′), 5.84 (1H, d, J=16.0 Hz, ═CH),5.02 (2H, d, J=4.0 Hz, CH₂O), 3.75 (2H, t, J=8.0 Hz, OCH₂CH₂O), 3.45(2H, t, J=12.0 Hz, OCH₂CH₂O), 3.02 (3H, s, OCH₃), 2.15 (6H, s, 2×CH₃);MS m/z 499 (M+1).

EXAMPLE 33 Preparation ofN¹-(4′-cyanophenyl)-5-(4″-cyanovinyl-2″,6″-dimethylphenoxy)-4-(2-methoxyethoxyl)methyl-1,2-phenylenediamine(Compound 33)

Compound 32 was reduced with Na₂S₂O₄ (Method B in Preparation Example 3)to get Compound 33, with a yield of 22%, as a white solid. ¹HNMR δ ppm2.13 (6H, s, 2×CH₃), 3.21 (3H, s, OCH₃), 3.46 (2H, t, J=7.0 Hz, CH₂O),3.68 (4H, s, OCH₂, NH₂), 4.88 (2H, s, CH₂), 5.79 (1H, d, J=16.4 Hz,═CH), 5.98 (1H, s, ArH-6), 6.51 (2H, d, J=8.8 Hz, ArH-2′,6′), 6.95 (1H,s, ArH-3), 7.17 (2H, s, ArH-3″,5″), 7.30 (1H, d, J=16.8 Hz, CH═),7.37(2H, d, J=7.2 Hz, ArH-3′,5′); MS m/z (%) 483.4 (M+1, 47), (M+Na,100).

EXAMPLE 34 Preparation of5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-(2-cyclopropylaminomethyl)-1,2-phenylenediamine(Compound 34)

By reference to the method in Example 31, Compound 5 (1 g, 2.27 mmol)and cyanuric chloride (627 mg, 3.41 mmol) were used to prepare thecorresponding chloro compound (800 mg), with a yield of 77%. Thechloride (200 mg, 0.44 mmol) was dissolved in acetonitrile,cyclopropylamine (3 drops) was added in the condition of ice bath, andthe reaction was carried out at room temperature. After the reactionfinished as monitored by TLC, the corresponding nitro compound (130 mg)was isolated with a yield of 62%. The nitro compound (110 mg, 0.23 mmol)was subjected to catalytic hydrogenation (Method A in PreparationExample 3) in ethanol to get Compound 34 (60 mg), with a yield of 58%,as a white solid. ¹HNMR δ ppm 0.48 (4H, m, CH₂CH₂), 2.10 (6H, s, 2×CH₃),2.23 (1H, m, CH), 2.14 (2H, t, J=7.0 Hz, CH₂CN), 2.88 (2H, t, J=7.0 Hz,ArCH₂), 3.53 (2H, s, NH₂), 3.99 (2H, s, ArCH₂), 5.51 (1H, s, NH), 6.02(1H, s, ArH-6), 6.54 (2H, d, J=8.8 Hz, ArH-2′,6′), 6.86 (1H, s, ArH-3),6.94 (2H, s, ArH-3″,5″), 7.40 (2H, d, J=9.2 Hz, ArH-3′,5′); MS m/z (%)354.1 (M−98, 100), 474.0 (M+Na, 10).

EXAMPLE 35 Preparation of5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-amino-1,2,4-triaminobenzene(Compound 35)

Compound5-(4″-cyanovinyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-2,4-dinitroaniline(please refer to J. Med. Chem. 2010, 51,8287-8296 for the preparationmethod thereof) was subjected to catalytic hydrogenation (Method A inPreparation Example 3) to get Compound 40, with a yield of 70%; whitesolid; m.p. 118-20° C., ¹H NMR δ ppm 2.11 (6H, s, 2×CH₃), 2.61 (2H, t,J=7.2 Hz, CH₂CN), 2.86 (2H, t, J=7.2 Hz, CH₂Ar), 5.36 (1H, s, NH), 5.94(1H, s, ArH-6), 6.30 (1H, s, ArH-3), 6.48 (2H, d, J=8.8 Hz, ArH-2′,6′),6.91 (2H, s, ArH-3″,5″), 7.37 (2H, d, J=8.8 Hz, ArH-3′,5′); MS m/z (%)398 (M+1, 100).

EXAMPLE 36 Preparation of5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-formhydrazide-1,2-phenylenediamine(Compound 36)

Compound 7 (140 mg, 0.30 mmol) was reacted with SOCl₂ (0.50 mL) and thendissolved in dried THF (3 mL), and aqueous hydrazine hydrate solution(85%, 1 mL) was slowly added dropwise at room temperature, understirring for 1 h. The crude product obtained by post-treatment wasisolated through silica gel column chromatography (MeOH/CH₂Cl₂) to get116 mg of diarylnitrobenzene compound, which was subjected to catalytichydrogenation (Method A in Preparation Example 3) to get Compound 36,with a yield of 75%, as a white solid; ¹H NMR δ ppm 2.11 (6H, s, 2×CH₃),2.61 (2H, t, J=6.8 Hz, CH₂CN), 2.86 (2H, t, J=6.8 Hz, CH₂Ar), 6.21 (1H,s, ArH-6), 6.30 (1H, s, NH), 6.48 (2H, d, J=8.8 Hz, ArH-2′,6′), 6.98(2H, s, ArH-3″,5″), 7.00 (1H, s, ArH-3), 7.43 (1H, d, J=8.8 Hz,ArH-3′,5′); MS m/z (%) 441 (M+1, 100).

EXAMPLE 37 Preparation of4-acetyloxymethyl-N¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-1,2-phenylenediamine(Compound 37)

Compound 5 (93 mg, 0.21 mmol), sodium hydroxide (30 mg, 0.75 mmol) and 3ml of acetic acid were placed in a microwave tube, and heated bymicrowave at 100° C. for 5 min. The reaction solution was poured into asuitable amount of ice-water, and stirred at room temperature, andyellow solid was precipitated. Sucking filtration was performed to getthe ester compound (93 mg, yellow solid), with a yield of 95%. Thecompound (80 mg, 0.17 mmol)was subjected to catalytic hydrogenation(Method A in Preparation Example 3) in ethanol to get 30 mg of Compound37, with a yield of 40.0% as a white solid. ¹HNMR (DMSO-d₆) δ ppm 2.04(6H, s, 2×CH₃), 2.09 (3H, s, COCH₃), 2.78 (4H, s, ArCH₂CH₂CN), 4.58 (2H,s, NH₂), 5.19 (2H, s, CH₂O), 5.90 (1H, s, NH), 6.54 (2H, d, J=9.2 Hz,ArH-2′,6′), 6.87 (1H, s, ArH-6), 7.04 (2H, s, ArH-3″,5″), 7.45 (2H, d,J=8.8 Hz, ArH-3′,5′), 8.08 (1H, s, ArH-3); MS m/z (%) 395.2(M−59, 100),455.3 (M+1, 17).

EXAMPLE 38 Preparation ofN¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-4-methoxymethyl-1,2-phenylenediamine(Compound 38)

Compound 5 (110 mg, 0.25 mmol) was dissolved in dichloromethane, andthen was added to a mixture of CCl₄, bismuth chloride (98 mg, 0.31 mmol)and methanol. After stirring at room temperature for 2-6 h, undissolvedsubstance was filtered out, and the organic phase was dried overanhydrous sodium sulfate, and isolated and purified to get 80 mg methylether nitro compound, with a yield of 61%, as a yellow solid. The nitrocompound (150 mg, 0.33 mmol) was subjected to catalytic hydrogenation(Method A in Preparation Example 3) in ethanol to prepare Compound 38(110 mg), with a yield of 79%, % as a white solid. ¹HNMR (CDCl₃) δ ppm2.09 (6H, s, 2×CH₃), 2.61(2H, t, J=7.2 Hz, CH₂CN), 2.87(2H, t, J=7.2 Hz,ArCH₂), 3.52 (3H, s, OCH₃), 4.67 (2H, s, CH₂O), 5.56 (1H, s, NH), 6.03(1H, s, ArH-6), 6.55 (2H, d, J=8.8 Hz, ArH-2′,6′), 6.92 (2H, s,ArH-3″,5″), 6.99 (1H, s, ArH-3), 7.39 (2H, d, J=8.8 Hz, ArH-3′,5′); MSm/z (%) 427.3 (M+1, 100).

EXAMPLE 39 Preparation ofN¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-4-cyclopropionyloxymethyl-1,2-phenylenediamine(Compound 39)

Compound 5 (80 mg, 0.18 mmol) was dissolved in dichloromethane, andcyclopropionylchloride (28.6 mg, 0.27 mmol) and pyridine (1 ml) wereadded. After stirring at room temperature for 4 h, the reactionfinished. The resultant solution was washed with 5% hydrochloric acid,washed with water, dried with anhydrous sodium sulfate, concentratedunder reduced pressure, and isolated through preparative silica gelplate or column to get 74 mg of nitro compound (yellow solid), with ayield of 89%. The nitro compound (180 mg) was subjected to catalytichydrogenation (Method A in Preparation Example 3) to get 35 mg ofCompound 29, with a yield of 21%, as a white solid. ¹HNMR δ ppm 0.90(2H, m, CH₂), 1.06 (2H, m, CH₂), 1.70 (1H, m, CH), 2.10 (6H, s, 2×CH₃),2.61 (2H, t, J=6.8 Hz, CH₂CN), 2.87 (2H, t, J=7.4 Hz, ArCH₂), 3.48 (2H,s, NH₂), 5.31 (2H, s, CH₂O), 5.56 (1H, s, NH), 6.06 (1H, s, ArH-6), 6.58(2H, d, J=8.8 Hz, ArH-2′,6′), 6.92 (3H, s, ArH-3,3″,5″), 7.41 (2H, d,J=8.8 Hz, ArH-3′,5′).

EXAMPLE 40 Preparation ofN¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-4-[N,N-dimethylaminomethyl]-1,2-phenylenediamine(Compound 40)

Compound 5 (1 g, 2.27 mmol) and cyanuric chloride (627 mg, 3.41 mmol)were used to prepare the corresponding chloro compound (800 mg) byreference to the method of Example 31, with a yield of 77%. The chloride(200 mg, 0.44 mmol) was then dissolved in acetonitrile, and aqueousdimethylamine solution (33%, 5 drops) was added in the condition of icebath. After the reaction (under the conditions that were the same asthose in Example 34) finished, the corresponding nitro compound (110 mg)was obtained by isolation, with a yield of 54%. The nitro compound (100mg, 0.21 mmol) was subjected to catalytic hydrogenation in ethyl acetate(Method A in Preparation Example 3) to get 70 mg of Compound 40, with ayield of 74%, as a light yellow solid. ¹HNMR δ ppm 2.08 (6H, s, 2×CH₃),2.39 (6H, s, 2×CH₃), 2.61 (2H, t, J=7.2 Hz, CH₂CN), 2.87 (2H, t, J=7.2Hz, ArCH₂), 3.67 (2H, s, ArCH₂), 5.51 (1H, s, NH), 6.02 (1H, s, ArH-6),6.54 (2H, d, J=8.8 Hz, ArH-2′,6′), 6.94 (2H, s, ArH-3″,5″), 7.01 (1H, s,ArH-3), 7.40 (2H, d, J=9.2 Hz, ArH-3′,5′); MS m/z (%) 395.2 (M−45, 100).

EXAMPLE 41 Preparation ofN¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-4-[N-ethylformamido]-1,2-phenylenediamine(Compound 41)

Compound 7 (300 mg, 0.66 mmol) was dissolved in thionyl chloride (10 mL)and was cooled to room temperature after reflux for 4 h, the reactionsolution was poured into petroleum ether, standed for 10 min, andfiltered to get a yellow solid. The solid was dissolved in THF (10 mL),and was cooled to 0° C. Aqueous ethylamine solution (3 drops, 65-75%)was added, and stirred at room temperature for 1 h. The reactionsolution was washed with water, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The crude product was purifiedthrough column chromatography to get 130 mg of yellow solid, with ayield of 41%. The nitro compound (120 mg, 0.25 mmol) was subjected tocatalytic hydrogenation in ethyl acetate (Method A in PreparationExample 3) to get 68 mg of Compound 41, with a yield of 60%, as a whitesolid. ¹H NMR δ ppm 1.24 (3H, t, J=7.2 Hz, CH₃), 2.13 (6H, s, 2×CH₃),2.60 (2H, t, J=7.2 Hz, CH₂CN), 2.89 (2H, t, J=7.0 Hz, ArCH₂), 3.55 (2H,m, J=7.2 Hz, J=5.6 Hz, NHCH₂), 5.88 (1H, s, NH), 6.21 (1H, s, ArH-6),6.70 (2H, d, J=8.8 Hz, ArH-2′,6′), 6.84 (1H, s, ArH-3), 7.00 (2H, s,ArH-3″,5″), 7.41 (2H, d, J=9.2 Hz, ArH-3′,5′), 7.82 (1H, s, ArH-3), 7.98(1H, t, J=5.6 Hz, CONH); MS m/z (%) 454.4 (M+1, 100).

EXAMPLE 42 Preparation ofN¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-4-[N,N-dimethylformamido]-1,2-phenylenediamine(Compound 42)

The preparation method was the same as the one in Example 41. Compound 7(300 mg, 0.66 mmol) was subjected to chloroformylation reaction, and wassubjected to amidation with aqueous dimethylamine solution (5 drops,33%) to get the corresponding nitro compound (249 mg), with a yield of79%, as a yellow solid. The nitro compound (227 mg, 0.47 mmol) wassubjected to catalytic hydrogenation in ethyl acetate (Method A inPreparation Example 3, 24 h) to get 156 mg of Compound 42, with a yieldof 78%, as a white solid. ¹H NMR (CDCl₃) δ ppm 2.10 (6H, s, 2×CH₃), 2.60(2H, t, J=7.2 Hz, CH₂CN), 2.86 (2H, t, J=7.2 Hz, ArCH₂), 3.10 (3H, s,CH₃), 3.16 (3H, s, CH₃), 3.60 (2H, s, NH₂), 5.77 (1H, s, NH), 6.12 (1H,s, ArH-6), 6.60 (2H, d, J=8.8 Hz, ArH-2′,6′), 6.84 (1H, s, ArH-3), 6.92(2H, s, ArH-3″,5″), 7.39 (2H, d, J=9.2 Hz, ArH-3′,5′); MS m/z (%) 454(M+1, 100).

EXAMPLE 43 Preparation ofN¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-4-[N-cyclopropylformamido]-1,2-phenylenediamine(Compound 43)

The preparation method was the same as the one in Example 41. Compound 7(250 mg, 0.55 mmol) was subjected to chloroformylation reaction, andthen was subjected to amidation with cyclopropylamine (0.1 mL) to getthe corresponding nitro compound (170 mg), with a yield of 63%, as ayellow solid. The nitro compound (150 mg, 0.3 mmol), was subjected tocatalytic hydrogenation in ethyl acetate (Method A in PreparationExample 3, about 7 h) to get Compound 43 (115 mg), with a yield of 82%,as a white solid. ¹H NMR (CDCl₃) δ ppm 1.42 (4H, 2×CH₂), 2.08 (6H, s,2×CH₃), 2.17 (1H, m, CH), 2.60 (2H, t, J=7.2 Hz, CH₂CN), 2.86 (2H, t,J=7.2 Hz, ArCH₂), 4.66 (2H, br, NH₂), 5.53 (1H, br, NH), 6.02 (1H, s,ArH-6), 6.54 (2H, d, J=8.8 Hz, ArH-2′,6′), 6.91 (2H, s, ArH-3″,5″), 6.97(1H, s, ArH-3), 7.39 (2H, d, J=8.8 Hz, ArH-3′,5′); MS m/z (%) 466 (M+1,100).

EXAMPLE 44 Anti-HIV Activity Assay (TZM-bl Cell Model)

The assay was carried out by reference to the document (Dang, Z, et al.J. Med. Chem. 2009, 52, 7887-7891). In particular, in a 96-well cellculture plate, solutions of the compounds to be tested at differentconcentrations were mixed with TZM-bl cells (from National Institutes ofHealth (NIH)) infected with 200 TCID50 NL4-3 virus, respectively. 2 dayslater, the culture medium was removed, 100 μl of Bright Glo reagent wasadded to each well, and Victor 2 luminometer was used to detect thefluorescence of the cells. CalcuSyn software was used to calculate the50% effective concentration (EC₅₀) of the compounds. The results areshown in Table 2.

TABLE 2 Anti-HIV activity of some compounds of formula I according tothe invention (NL4-3HIV-wild) EC₅₀ CC₅₀ Compound (μM)^(a) (μM)^(b)SI^(c)  2 0.00113 >7.1 >6,283  4 0.0043 >22.7 >5255  6 0.00039 >23.861026 10 0.00139 >9.4 >6762 12 0.00273 >9.1 >3330 16 0.0147 16.4 1116 180.0100 >15.9 >1590 21 0.0028 >10.2 >3643 23 0.099 >15.3 >155 240.048 >25.2 >525 26A 0.00325 21 6563 26B 0.0257 21.3 1207 28 0.000338.21 24878 30 0.0047 >9.8 >2130 33 0.0213 >5 >235 34 0.00053 >5 >9434 350.0061 >5 >820 36 0.0191 >22.7 >1188 37 0.00329 >5 >1520 380.00218 >5 >2293 39 0.00163 >5 >3067 40 0.00273 >5 >1832 410.00463 >5 >1080 42 0.00617 >5 >810 43 0.00133 >5 >3760 ^(a)aconcentration effective to inhibit the replication of half of viruses,which represents the anti-viral activity of a compound; ^(b)aconcentration effective to inhibit the growth of half of cells, whichrepresents the cytotoxicity of a compound; ^(c)selective index of acompound, which is a ratio of toxic CC₅₀ value to active EC₅₀ value;

TABLE 3 Activity against drug-resistant viruses and drug-like propertiesof some high active compounds Water- Com- Drug-resistant viruses EC₅₀(nM) solubility ^(g) HLM ^(h) pound RTMDR^(e) K101E^(f) E138K^(f) μg/mLt_(1/2) min 2 3.2 47.6 34.4 0.33 55.7 4 4.1 14 7.5 1.21 186 6 1.8 3.42.9 18.8 20.9 12 8.0 14 10 8.28 55.7  26A 3.46 3.89 6.93 1.77 54.7 280.74 7.63 4.11 3.26 23.0 34 1.88 27.3 25.7 9.11 42.0 ^(e)multi-drugresistant viral strain of HIV-1 RT (provided by US NIH), comprising theamino acid mutation sites of RT enzyme, such as M41L, V106A, T215Y,etc., and resistant to anti-HIV drugs AZT, ddI, and non-nucleoside RTenzyme inhibitor; ^(f)mutated amino acids located at the binding sitesof HIV-RT non-nucleoside inhibitors; ^(g) water-solubility and logPvalue were the values actually measured at pH2.0 (see Edward H.Kerns andLi Di; Drug-like Properties: Concepts, Structure Design and Methods,pages 267, 283); ^(h) incubation experiment of human liver microsomes(see the literature of g, page 335).

EXAMPLE 45 TZM-bl Cytotoxicity Assay of Compounds

The assay was carried out by reference to the document (Dang, Z, et al.J. Med. Chem. 2009, 52, 7887-7891). In particular, in a 96-well cellculture plate, solutions of Compounds 1-57 at different concentrations(100 μl) were mixed with an equivalent volume of TZM-bl cells (fromNational Institutes of Health (NIH)) (5×10⁵/mL), and were incubated at37° C. for 4 d. 50 μl of freshly prepared XTT solution (1 mg/mL)containing 0.02 μM PMS was added. Optical density at 450 nm was measured4 h later. CalcuSyn software was used to calculate the 50% cytotoxicityconcentration (CC₅₀) of the compounds. The results are shown in Table 2.

The experimental results above show that the compounds of formula Iaccording to the invention are new compounds having a strong anti-HIVactivity and a good druggability. Hence, the compounds according to theinvention are prospective in developing a novel class of anti-HIV drugswith new structure.

Although the embodiments of the invention have been described in detail,a person skilled in the art would understand that a variety ofmodifications and replacements may be performed to the details accordingto all the teachings disclosed therein. These changes all fall into theprotection scope of the invention. The scope of the invention is definedby the claims and any equivalent thereof.

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein R₁ is —NH₂, —OH a halogen, —NO₂, —CN, —COOH, —SO₃H, —OCH₃, —CH₃ or —CF₃; R₂ is H; R₃ is H, OH, a halogen, —NH₂, cyano, triazo, ethynyl, —NO₂, —COOH, —SO₃H, —CF₃, vinyl, C₁₋₄ acyl, C₁₋₄ ester group, trifluoroacetoxyl, C₁₋₄ acyloxy, OCONH₂, OCONHCH₃, uramido, guanido, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆ aminoalkyl, C₁₋₆ ether alkyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkoxy, C₁₋₆ haloalkoxy, C₁₋₆ aminoalkoxy, C₁₋₆ ether alkoxy, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆ ether alkylamino, C₃₋₈ cycloalkyl, C₃₋₈ cyclylalkoxy, C₃₋₈ cyclylalkylamino, heterocyclyl, 3- to 8-membered heterocyclyl substituted by C₁₋₄ hydroxyalkyl or C₁₋₄ haloalkyl or C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl, 3- to 8-membered heterocyclylalkyl substituted by C₁₋₄ hydroxyalkyl or C₁₋₄ haloalkyl or C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl, 3- to 8-membered heterocyclylalkoxy substituted by C₁₋₄ hydroxyalkyl or C₁₋₄ haloalkyl or C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl, or 3- to 8-membered heterocyclylalkylamino substituted by C₁₋₄ hydroxyalkyl or C₁₋₄ haloalkyl or C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl; R₄ is —CN, —NH₂, —OH, a halogen, —NO₂, —COOH, —SO₃H, —OCH₃, —CH₃, —CF₃, vinyl, ethynyl, triazo, cyanovinyl or cyanoethynyl; R₅ is C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen or C₁₋₆ haloalkyl; R₆ is C₁₋₆ alkyl, C₁₋₆ alkoxy, a halogen or C₁₋₆ haloalkyl; R₆ and R₅ are identical or different; R₇ is —NH₂, —OH, a halogen, —NO₂, —CN, —COOH, —SO₃H, —OCH₃, —CH₃, —CH═CH—CN, or —CF₃; or R₇ is —NH₂, —OH, a halogen, —NO₂, —CN, —OCH₃, —CH₃, —CH═CH—CN, or —CF₃, linked to 1, 2, 3, or 4 —CH₂—; or R₇ is C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆ cyanoalkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆ ether alkoxy, C₂₋₆ alkenyl or alkynyl, ene-ene-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl, ene-yne-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl, ene-carbonyl-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl, yne-carbonyl-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl, C₁₋₆ hydrocarbonyl substituted with one or more hydroxyl or halogen; X is —NH— or —O—; Y is —CH— or —N—; and m is 0, 1, 2, 3 or
 4. 2. A compound of formula (II) or pharmaceutically acceptable salt thereof,

wherein R₁ is —NH₂, —OH, a halogen, —NO₂, —CN, —COOH, —SO₃H, —OCH₃, —CH₃ or —CF₃; R₂ is H; R₃ is H, OH, a halogen, —NH₂, cyano, triazo, ethynyl, —NO₂, —COOH, —SO₃H, —CF₃, vinyl, C₁₋₄ acyl, C₁₋₄ ester group, trifluoroacetoxyl, C₁₋₄ acyloxy, OCONH₂, OCONHCH₃, uramido, guanido, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆ aminoalkyl, C₁₋₆ ether alkyl, C₁₋₆ alkoxy, C₁₋₆ hydroxyalkoxy, C₁₋₆ haloalkoxy, C₁₋₆ aminoalkoxy, C₁₋₆ ether alkoxy, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆ ether alkylamino, C₃₋₈ cycloalkyl, C₃₋₈ cyclylalkoxy, C₃₋₈ cyclylalkylamino, heterocyclyl, 3- to 8-membered heterocyclyl substituted with C₁₋₄ hydroxyalkyl or C₁₋₄ haloalkyl or C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl, 3- to 8-membered heterocyclylalkyl substituted with C₁₋₄ hydroxyalkyl or C₁₋₄ haloalkyl or C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl, 3- to 8-membered heterocyclylalkoxy substituted with C₁₋₄ hydroxyalkyl or C₁₋₄ haloalkyl or C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl, or 3- to 8-membered heterocyclylalkylamino substituted with C₁₋₄ hydroxyalkyl or C₁₋₄ haloalkyl or C₁₋₄ aminoalkyl or C₁₋₄ cyanoalkyl or C₁₋₄ ether alkyl; R₄ is H, —CN, —NH₂, —OH, a halogen, —O₂, —COOH, —SO₃H, —OCH₃, —CH₃, —CF₃, vinyl, ethynyl, triazo, cyanovinyl or cyanoethynyl; R₅ and R₆ each are independently C₁₋₆ alkyl, C₁₋₆ alkoxy; a halogen or C₁₋₆ haloalkyl; R₆ and R₅ are identical or different; R₇ is —NH₂, —OH, a halogen, —NO₂, —CN, —COOH, —SO₃H, —OCH₃, —CH₃, —CH═CH—CN, or —CF₃; or R₇ is —NH₂, —OH, a halogen, —NO₂, —CN, —OCH₃, —CH₃, —CH═CH—CN, or —CF₃, linked to 1, 2, 3, or 4 —CH₂—; or R₇ is C₁₋₆ aminoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆ cyanoalkyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₁₋₆ ether alkoxy, C₂₋₆ alkenyl or alkynyl, ene-ene-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl, ene-yne-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl, ene-carbonyl-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl, yne-carbonyl-containing conjugated or non-conjugated C₂₋₆ hydrocarbonyl, C₁₋₆ hydrocarbonyl substituted with one or more hydroxyl or halogen; m is 0, 1, 2 or 3; X is —NH— or —O—; and Y is —CH— or —N—.
 3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R₁ is —NH₂, —OH, —F, —Cl, —Br, —I, —NO₂, —CN, —COOH, —SO₃H, —OCH₃, —CH₃ or —CF₃; R₂ is H; R₃ is —CF₃, —CCl₃, —CBr₃, —COOCH₃, —COOCH₂CH₃, —COOCH₂CH₂CH₃, —COOH, —CONH₂, —CONHCH₃, —SO₂NH₂, H, —NH₂, —CONHNH₂, —OH, —F, —Cl, —Br, —I, —NO₂, —CN, —SO₃H, —OCH₃, —CH₃, CH₂OH, CH₂Cl, CH₂NH₂, CH₂OR′, or —CH₂NHR′; wherein R′ is

R₄ is —CN, —NH₂, —OH, —F, —Cl, —Br, —I, —NO₂, —COOH, —SO₃H, —OCH₃, —CH₃ or —CF₃; R₅ is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoro, chloro, bromo, or iodo; R₆ is methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoro, chloro, bromo, or iodo; R₆ and R₅ are identical or different; R₇ is

wherein R″ represents C₁₋₆ alkyl; X is —NH— or —O—; and Y is —CH— or —N—.
 4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R₁ is —NH₂; R₂ is H; R₃ is —CF₃, —COOCH₃, —COOH, —CONH₂, —CONHCH₃, —SO₂NH₂, H, —NH₂, —CONHNH₂; —OH, —F, —Cl, —Br, —I, —NO₂, —CN, —SO₃H, —OCH₃, —CH₃, —CH₂OH, —CH₂OR′, —CH₂NH₂, —CH₂NHR′, —CH₂Cl or —CH₂Br; R₄ is —CN; R₅ is methyl, methoxy, fluoro, chloro, or bromo; R₆ is methyl, methoxy, fluoro, chloro, or bromo; R₆ and R₅ are identical or different; R₇ is

X is —O—; and Y is —CH— or —N—.
 5. The compound or pharmaceutically acceptable salt thereof according to claim 1, selected from the following compounds or pharmaceutically acceptable salts thereof: 5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-trifluoromethyl-1,2-phenylenediamine; 5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-methoxycarbonyl-1,2-phenylenediamine; 5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-hydroxymethyl-1,2-phenylenediamine; 4-carboxyl-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-1,2-phenylenediamine; 4-carbamoyl-N¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-1,2-phenylenediamine; 5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-(N-methyl-carbamoyl)-1,2-phenylenediamine; 5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-aminosulfonyl-1,2-phenylenediamine; N²-(4-cyanoanilinyl)-6-(2,6-dimethyl-4-propylphenoxy)-3-aminopyridine; N-(4′-cyanophenyl)-5-(4″-hydroxymethyl-2″,6″-dimethylphenoxy)-4-hydroxymethyl-2-nitroaniline; N¹-(4′-cyanophenyl)-5-(4″-hydroxymethyl-2″,6″-dimethylphenoxy)-4-hydroxymethyl-1,2-phenylenediamine; N²-(4-cyanoanilinyl)-6-(2,6-difluoro-4-cyanoethyl-phenoxy)-3-aminopyridine; N²-(4-cyanoanilinyl)-6-(2,6-difluoro-4-methyl propionate phenoxy)-3-aminopyridine; N²-(4-cyanoanilinyl)-6-(2,6-difluoro-4-(3-hydroxypropyl)phenoxy)-3-aminopyridine; 6-(2-bromo-4-cyanoethyl-5-methoxy)phenoxy-2-(4-cyanoanilinyl)-3-aminopyridine; 6-(2-bromo-4-cyanovinyl-5-methoxy)phenoxy-2-(4-cyanoanilinyl)-3-aminopyridine; 2-(4-cyanoanilinyl)-6-(2,6-dibromo-4-cyanoethyl)phenoxy-3-aminopyridine; N²-(4-cyanoanilinyl)-6-(2,6-difluoro-4-butanonylphenoxy)-3-aminopyridine; N¹-(4′-cyanophenyl)-5-(4″-cyanovinyl-2″,6″-dimethylphenoxy)-4-[(2-methoxyethoxyl)methyl]-1,2-phenylenediamine; N¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-4-[N-cyclopropylaminomethyl]-1,2-phenylenediamine; N¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-1,2,4-triaminobenzene; N¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-4-formhydrazide-1,2-phenylenediamine; 4-acetyloxymethyl-N¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-1,2-phenylenediamine; N¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-4-[methoxymethyl]-1,2-phenylenediamine; N¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-4-cyclopropionyloxymethyl-1,2-phenylenediamine; N¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-4-[N,N-dimethylaminomethyl]-1,2-phenylenediamine; N¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-4-(N-ethylformamido)-1,2-phenylenediamine; 5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-N¹-(4′-cyanophenyl)-4-(N,N-dimethylformamido)-1,2-phenylenediamine; and N¹-(4′-cyanophenyl)-5-(4″-cyanoethyl-2″,6″-dimethylphenoxy)-4-(N-cyclopropylformamido)-1,2-phenylenediamine.
 6. A method for preparing the compound or pharmaceutically acceptable salt thereof according to claim 1, the method comprising the scheme as follows:

and the method comprising: reacting a substituted 2,6-dihalo benzene or pyridine compound with a p-substituted aniline compound under a basic condition, or using excessive 4-cyano aniline to carry out a solvent-free reaction to produce the intermediate of formula II or III; coupling with a 1,3,5-trisubstituted phenol or aniline compound under a basic condition to get an intermediate (IV or V) having a tricycle backbone structure, then converting the substituent (R₁) of the intermediate ring to the corresponding group through conventional functional-group group conversion reaction, and finally reducing the nitro group on the intermediate ring to an amino group.
 7. A pharmaceutical composition, comprising the compound or pharmaceutically acceptable salt thereof according to claim 1; and, optionally, one or more pharmaceutically acceptable carriers or excipients.
 8. (canceled)
 9. A method for prevention and/or treatment and/or assistant treatment of HIV or a disease or condition associated with HIV infection, comprising the step of administering an effective amount of the compound or pharmaceutically acceptable salt thereof according to claim 1 to a subject.
 10. (canceled)
 11. A method for inhibiting HIV virus in vivo or in vitro, comprising the step of using an effective amount of the compound or pharmaceutically acceptable salt thereof according to claim
 1. 